BIOLOGY 
LIBRARY 

G 


GLANDS 

IN  HEALTH  AND  DISEASE 


BY 

BENJAMIN  HARROW,  Pn.D. 

ASSOCIATE    IN    PHYSIOLOGICAL    CHEMISTRY,    COLLEGE 

OF  PHYSICIANS  AND  SURGEONS, 

COLUMBIA   UNIVERSITY 


NEW  YORK 

E.  P.  DUTTON  &  COMPANY 
681  FIFTH  AVENUE 


COPYRIGHT, 

BY  E.  P.  DUTTON  &  COMPANY 


All  Rights  Reserved 


BIOLOG^ 


Printed  in  the  United  States  of  America 


PINEAL 
PITUITARY 


(feRATHYftOtlXS 
THYROIp 

THYMUS 


SPLEEN ,L • 


..LIVER 
-.PANCREAS 


—I— ADRENALS 


-,,...  REPRODUCTIVE 
ORQAN5 


THE  DUCTLESS  GLANDS 


To 
PROFESSOR  WILLIAM  J.  GIES 

TEACHER  AND   JRIEND 


PREFACE 

Monkey  glands;  clever  men  and  stupid  ones; 
glands  as  the  cause  of  crime;  the  origin  of  races;  the 
mentally  unbalanced;  many  acute  diseases;  "the 
bearded  lady,  the  giant,  the  fat  boy  and  the  midget" ; 
— all  these  and  more  have  been  dealt  with  under  the 
subject  of  glands  of  internal  secretion  (also  called 
ductless  or  endocrine  glands).  As  in  any  subject 
that  fires  the  popular  imagination,  fact  and  fancy 
have  been  mixed, — several  drops  of  fact  have  been 
largely  diluted  with  many  drops  of  fancy.  The 
achievements,  judged  by  rigid  scientific  standards, 
are  no  more  than  modest,  but  the  possibilities  are 
limitless.  It  is  because  of  these  vast  possibilities 
that  an  imagination,  not  sufficiently  tempered  by 
self-criticism,  is  apt  to  enlarge  a  molehill  into  a 
mountain. 

The  glands  discussed  in  this  book,  the  ductless  or 
endocrine  glands,  regulate  the  activities  of  the  or- 
ganism little  less  than  does  the  brain  itself.  Let  but 
one  of  these  bodies  stop  functioning,  or  let  it  func- 
tion imperfectly,  and  injuries  to  various  parts  of  the 


IX 


x  PREFACE 

body  become  manifest.  Since  glandular  disorders 
are  among  the  commonest  causes  of  disease,  ranging 
from  slight  mental  or  physical  derangement  to  com- 
plete mental  or  physical  breakdown,  a  general  sur- 
vey of  the  subject,  told  in  popular  but  not  sensa- 
tional language,  faithfully  recording  what  has  been 
accomplished,  should  prove  of  interest.  There  is  a 
crying  need,  in  the  opinion  of  the  author,  of  simple, 
yet  clear  and  clean-cut  statements  of  scientific  work 
to  which  the  layman  can  refer.  The  half-baked 
knowledge  that  he  often  gets  at  present  is  worse 
than  no  knowledge  at  all. 

Not  the  least  interesting  part  of  this  fascinating 
field  of  research  is  the  evidence  we  possess  that  the 
activities  of  these  glands  are  dependent  upon  rela- 
tively simple  chemical  substances  contained  in  them, 
to  which  the  name  "hormones"  or  "chemical  mes- 
sengers" has  been  given.  Without  in  any  way  at- 
tempting to  exaggerate  their  importance,  we  may  say 
of  these  hormones  that  they  are  as  indispensable  to 
the  life  process  as  are  vitamines,  a  subject  treated 
by  the  author  in  an  earlier  volume. 

I  am  indebted  in  various  ways  to  the  following: 
Professor  W.  B.  Cannon  (Harvard) ;  Professor  W. 
J.  Gies  (Columbia);  Dr.  Max  Kahn  (Columbia); 
Dr.  E.  C.  Kendall  (Mayo  Clinic,  Rochester,  Minn.) ; 
Dr.  E.  G.  Miller,  Jr.  (Columbia) ;  Mr.  A.  L.  Robert; 
Mr.  Thomas  Spector;  Professor  G.  N.  Stewart 


PREFACE  xi 

(Western  Reserve  Univ.) ;  and  Mrs.  N.  J.  Waller- 
stein.  Dr.  Kendall,  Prof.  Stewart  and  Mrs.  Wal- 
lerstein  have  been  kind  enough  to  read  the  manu- 
script and  to  offer  several  helpful  suggestions. 

BENJAMIN  HARROW. 


CONTENTS 

CHAPIEB  PAGB 

I    INTRODUCTORY     .     .     .     .     .:    .    >    w    ..  1 

II    THE  THYROID ^    .     .  14 

III  THE  PARATHYROIDS       ....     .     .     .  43 

IV  THE  PITUITARY  GLAND     ......  47 

V    THE  ADRENAL  GLANDS 70 

VI    THE  ORGANS  OF  REPRODUCTION    ....  89 

VII    THE  PANCREAS  AND  THE  LIVER   ....  115 

VIII    THE  INTESTINAL  HORMONE    .....  127 

IX    THYMUS,  SPLEEN,  MAMMARY  GLAND,  AND 

KIDNEY 135 

X    THE  RELATION  OF  THE  DUCTLESS  GLANDS 

TO  ONE  ANOTHER 147 

XI    THE  INFLUENCE  OF  THE  DUCTLESS  GLANDS 

ON  GROWTH  AND  METABOLISM  ....  156 

XII    THE  NERVOUS  SYSTEM  AND  THE  DUCTLESS 

GLANDS 158 

XIII  ORGANOTHERAPY 185 

XIV  PLANT  HORMONES 190 

REFERENCES 195 

INDEX 213 

xiii 


GLANDS  IN  HEALTH 
AND  DISEASE 


CHAPTEE  I 

INTRODUCTORY 

An  analogy. — The  Headquarters  Staff  is  often 
spoken  of  as  the  "brains"  of  the  army.  We  can 
speak  with  equal  justice  of  the  brain  as  the  Head- 
quarters Staff  of  an  army  consisting  of  the  millions 
of  cells  of  the  body.  These  cells  are  organized  in 
units  made  up  of  army  corps,  just  as  every  modern 
army  is ;  only  in  the  body  such  units  are  spoken  of 
as  "organs." 

We  can  carry  the  analogy  one  step  further.  The 
movements  of  the  several  army  corps,  it  is  true,  are 
controlled  by  the  Headquarters  Staff;  but  it  must 
be  evident  that  for  complete  cooperation,  not  only 
should  the  units  be  in  touch  with  the  General  Staff, 
but  also  with  one  another.  If  the  Staff  breaks 
down,  the  army  goes  to  pieces;  if  connections  be- 
tween the  several  units  are  broken  off,  the  army 
also  goes  to  pieces.  Likewise  with  the  body :  a  dis- 

1 


2          GLANDS  IN  HEALTH  AND  DISEASE 

turbance  in  the  brain  immediately  registers  its 
effect  on  the  rest  of  the  body;  so  does  a  breaking- 
off  of  communications  between  the  organs  of  the 
body. 

Now  while  we  have  long  been  familiar  with  the 
functions  of  the  brain,  we  have  not  until  recently 
been  aware  of  distinct  means  of  intercommunica- 
tion between  the  organs  themselves,  apart  from 
their  connection  with  the  brain.  The  study  of  the 
ductless  glands — the  subject  of  this  book — has  led 
to  this  discovery,  and  with  it  the  origin  of  a  number 
of  diseases  has  been  made  clear. 

Glands. — When  food  is  taken  into  the  mouth  it 
is  met  by  a  fluid  called  the  saliva.  Where  does  this 
fluid  come  from,  and  what  is  its  function?  This 
fluid,  this  saliva,  is  manufactured  in  factories  situ- 
ated in  front  of  the  ears  and  between  the  lower 
jaw  and  the  floor  of  the  mouth.  The  factories  get 
their  raw  materials  from  the  blood,  and  the  cells 
in  these  factories  convert  the  raw  materials  into  a 
product  which  we  call  saliva.  Tubes  connecting 
these  factories  with  the  interior  of  the  mouth  enable 
the  manufactured  fluid  to  be  sent  to  the  mouth. 
These  tubes  are  spoken  of  as  "ducts." 

Now  what  is  the  function  of  this  saliva,  the 
product  of  cellular  activity  in  these  factories  or 
"glands"  of  the  body?  It  has  in  reality  several 
functions,  but  there  is  one  that  stands  out  far  above 
the  others:  it  converts  the  starch  of  foods  into 


INTRODUCTORY  3 

chemically  simpler  products.  This  conversion  is 
due  to  the  presence  in  the  saliva  of  "ptyalin,"  a 
substance  that  belongs  to  a  class  of  compounds 
known  as  "enzymes"  or  "ferments."  Much  of  the 
chemical  work  of  the  body — and  this  includes  the 
plant  as  well  as  the  animal  kingdom — is  due  to  the 
activity  of  these  enzymes. 

A  gland,  then,  is  an  organ  that  has  the  power  of  I 
taking  certain  materials  from  the  blood  and  manu-  / 
facturing  from    these   raw    materials   a   product/ 
which  plays  a  part  in  the  activities  of  the  body.' 
The  salivary  glands,  wherein  saliva  is  manufac- 
tured, are  an  example.    The  gastric  glands  lining 
the  wall  of  the  stomach,  manufacturing  gastric 
juice  for  the  stomach  needs,   are  another.     The 
pancreatic   and  intestinal   juices  arising,   respec- 
tively, from  the  pancreas  and  the  small  intestine, 
are  still  others.     These  examples  could  be  multi- 
plied. 

Ductless  or  endocrine  glands,  or  glands  of  inter- 
nal secretion. — So  far  we  have  been  considering 
glands  that  have  tubes  or  "ducts"  connecting  them 
with  an  outer  surface,  such  as  the  mouth  or  stom- 
ach. Glands  are  known,  however,  that  have  no  such 
ducts,  but  that  pass  their  products  directly  into  the 
blood  stream.  Such  glands  are  known  as  "duct- 
less" glands.  Sometimes  they  are  spoken  of  as 
glands  of  "internal  secretion,"  to  distinguish  them 
from  those  glands  with  ducts  whose  secretion  is 


4    GLANDS  IN  HEALTH  AND  DISEASE 

poured  out  on  a  surface.  Sometimes  they  are  called 
"endocrine"  glands,  "endocrine"  being  derived  from 
two  Greek  words  meaning  "to  separate  within"; 
that  is  to  say,  an  "internal  secretion."  1 

It  is  these  "ductless"  glands  that  constitute  the 
subject  matter  of  this  book ;  for  recent  research  has 
shown  us  that  they  play  an  enormously  important 
part  in  health  and  disease. 

That  the  brain  through  its  nervous  mechanism 
controls  the  various  parts  of  the  body  is  common 
knowledge  to-day;  but  that  any  portion  of  the 
body's  activity  should  not  be  directly  responsible 
to  the  brain  for  its  controlling  mechanism,  is  an 
idea  that  may  sound  revolutionary  enough.  Yet 
such  is  the  case;  and  to  illustrate  it,  a  classical 
experiment  due  to  Bayliss  and  Starling,  two  gifted 
English  physiologists,  will  be  described. 

An  illustration. — The  food  that  we  take  into  the 
mouth  passes  through  the  stomach  into  the  small 
intestine.  Here  the  food  meets  not  only  the  intesti- 
nal fluid,  but  also  the  fluids  coming  from  the  bile 
on  the  one  hand,  and  the  pancreas!  on  the  other. 
The  bile  and  the  pancreatic  fluid  are  led  into  the 
small  intestine  by  means  of  tubes.  Now  why  when- 
ever food  appears  in  the  small  intestine  do  bile  and 
pancreatic  juice  also  flow  into  it?  The  answer  un- 
til recently  was  considered  a  very  simple  one.  The 

1This  definition  does  not  take  into  account  the  conception  of 
the  histologist  as  to  what  constitutes  a  "glandular"  structure. 


INTRODUCTORY  5 

physiologists  said  that  the  nervous  mechanism 
controls  the  flow  of  the  fluids ;  that  whenever  food 
appears  in  the  intestine,  a  nervous  reaction  calls 
forth  the  flow  of  bile  and  pancreatic  juice.  Bayliss 
and  Starling  showed  that  this  conception  needed 
modification. 

These  investigators,  in  experimenting  with  dogs, 
cut  off  all  nervous  connections  with  the  small 
intestine;  yet  the  fluids  still  continued  to  flow  into 
it.  They  then  suspected  that  possibly  the  acid 
from  the  stomach,  upon  reaching  the  small  intes- 
tine, liberates  something  from  the  walls  of  the 
organ,  which  "something"  finds  its  way  to  the 
pancreas  and  the  bile,  and  thereby  gives  warning 
of  the  need  of  these  fluids.  They  thereupon  ex- 
tracted a  piece  of  the  intestinal  wall  with  hydro- 
chloric acid — which  is  the  acid  found  in  the 
stomach — and  injected  this  extract  into  the  blood 
stream.  There  was  an  immediate  and  copious  flow 
of  pancreatic  juice  into  the  intestine. 

What  then  happens  in  the  course  of  digestion 
in  the  small  intestine?  The  food  that  arrives  from 
the  stomach  is  acid,  due  to  the  hydrochloric  acid 
that  is  formed  in  the  stomach.  This  acid  liberates 
a  substance  present  in  an  otherwise  inactive  state 
in  the  wall  of  the  intestine,  and  this  substance 
travels  through  the  blood  to  the  pancreas,  where 
it  stimulates  that  organ  to  discharge  its  fluid. 

Hormones. — Note  that  all  this  is  performed  with- 


6          GLANDS  IN  HEALTH  AND  DISEASE 

out  any  help  from  the  brain.1  Note  that  one  organ 
of  the  body — the  intestine  in  our  example — manu- 
factures a  substance  which  finds  its  way  into  the 
blood  stream  and  affects  another  organ  of  the 
body,  the  pancreas.  Here  we  have  a  classical  ex- 
ample of  the  workings  of  a  ductless  gland;  for  in 
every  gland  of  the  ductless  variety  a  specific  sub- 
stance is  manufactured  that  finds  its  way  into  the 
blood  stream  and  influences  another  organ  or  or- 
gans of  the  body.  The  substance  so  manufactured 
is  called  a  "hormone"  (from  the  Greek  "to  excite" 
or  "arouse")  or  "chemical  messenger."  The  hor- 
mone in  the  intestinal  wall  has  been  given  the 
name  of  "secretin"  by  its  discoverers.  Without 
this  secretin  no  pancreatic  juice  could  find  its  way 
into  the  intestine,  and  without  pancreatic  juice 
no  digestion  of  food  could  take  place. 

The  small  intestine  is  an  example  of  a  tissue 
which  gives  rise  both  to  an  internal  and  an  ex- 
ternal secretion.  Its  internal  secretion,  the  secre- 
tin, has  already  been  described.  But  as  a  matter 
of  fact  it  also  develops  a  secretion,  the  intestinal 
juice,  which  is  carried  by  ducts  to  the  surface  of 
the  intestine,  in  the  same  way  that  salivary  or 

1 1  do  not  want  the  impression  to  be  conveyed  that  there  is  no 
connection  between  the  hormones  on  the  one  hand  and  the  nervous 
system  on  the  other.  As  a  matter  of  fact  there  are  connecting 
links,  as  the  chapter  on  nervous  disorders  will  attempt  to  make 
clear.  All  I  want  to  point  out  at  this  stage  is  that  a  particular 
mechanism,  for  which  the  brain  is  held  responsible,  can  be  ex- 
plained without  involving  the  brain  at  all. 


INTRODUCTORY  7 

gastric  juice  is,  and  which,  like  these  two,  plays  an 
important  role  in  the  digestion  of  foodstuffs. 

The  double  property  of  producing  both  an  in- 
ternal and  an  external  secretion,  which  character- 
izes the  small  intestine,  is  found  in  a  number  of 
other  tissues.  The  external  secretion  of  the  pan- 
creas, for  example,  is  the  pancreatic  juice,  which 
is  carried  by  means  of  a  duct  to  the  small  intestine. 
But  it  has  been  shown  that  the  removal  of  the 
pancreas,  or,  what  is  the  same  thing,  the  removal 
with  it  of  an  internal  secretion  developed  by  the 
organ,  and  which  finds  its  way  into  the  blood, 
gives  rise  to  the  dreaded  sugar  disease  commonly 
known  as  "diabetes."  It  would  seem,  therefore, 
that  the  utilization  of  sugar  by  the  liver — the  organ 
that  stores  sugar  and  gives  it  out  when  necessary — 
is  controlled  by  an  internal  secretion  developed 
by  the  pancreas. 

The  generative  glands  (ovary  and  testicle)  show 
an  internal  and  external  secretion.  The  external 
secretion  contributes  to  the  reproduction  of  the 
species;  the  internal  secretion  plays  a  part  in  the 
development  of  male  and  female  characteristics. 
One  has  but  to  think  of  the  eunuchs  in  oriental 
countries,  or  of  animals  from  which,  for  commer- 
cial reasons,  the  generative  glands  are  removed,  to 
realize  what  effects  are  produced  by  removal  of 
these  glands.  But  this  will  be  treated  more  ex- 
tensively later. 


8  GLANDS  IN  HEALTH  AND  DISEASE 

The  thyroid,  the  pituitary,  the  sexual  organs,  the 
adrenals,  all  contain  hormones,  and  much  of  the 
influence  these  organs  exert  upon  our  general  well- 
being  is  due  to  these  chemical  messengers. 

The  composition  of  hormones. — Just  what  the 
hormones  consist  of  is  not  clear  in  most  cases.  Yet 
the  physiological  chemist  has  been  able  to  isolate 
in  a  pure  condition  a  hormone  present  in  the  adre- 
nal glands,  and  another  in  the  thyroid;  and  the 
organic  chemist  has  been  able  to  start  with  very 
simple  chemicals  and  synthesize  these  hormones 
in  his  laboratory.  So  that  at  least  in  two  instances 
we  know  what  the  composition  of  a  chemical  mes- 
senger is;  and  the  organic  chemist  will  tell  you 
that  their  composition  is  by  no  means  terrifying. 

Relation  of  hormones  to  vitamines,  etc. — Ridic- 
ulously small  amounts  of  hormone  are  sufficient  to 
restore  the  normal  equilibrium  of  the  body.  That 
is  to  say,  where,  as  in  thyroid  deficiency,  the  di^ 
ease  can  be  cured  by  the  administration  of  the 
corresponding  hormone,  the  amount  necessary  is 
almost  infinitesimal.  Neither  is  the  percentage  of 
hormone  in  the  active  gland  anything  but  slight. 
For  example,  Kendall,  of  the  Mayo  Clinic  at 
Rochester,  found  that  he  had  to  use  6,550  pounds 
of  fresh  thyroid  in  order  to  get  one  ounce  of  thy- 
roxin,  the  thyroid  hormone ! 

These  facts  immediately  suggest  a  relation  be- 
tween hormones  and  vitamines,  and  6ther  sub- 


INTRODUCTORY  9 

stances  present  in  the  body  in  small  amounts,  but 
which  nevertheless  exert  powerful  effects — such  as 
the  enzymes  or  ferments. 

Vitamines,  as  every  reader  of  the  press  must 
know  by  this  time,  are  unknown  factors  in  food, 
probably  present  in  amounts  that  defy  weighing 
by  the  ordinary  chemical  balance.  They  are  neces- 
sary for  a  continuation  of  the  life  cycle.  As  I  have 
said  elsewhere,1  without  vitamines  there  can  be  no 
life. 

To  what  extent  are  we  justified  in  comparing 
vitamines  with  hormones?  As  we  have  indicated, 
both  are  present  in  minute  quantity,  and  a  small 
quantity  seems  to  go  a  long  way.  Both  are  there- 
fore "catalytic"  in  their  action;  that  is  to  say, 
they  accelerate  or  hasten  chemical  action,  without 
themselves  undergoing  any  permanent  change. 

There  are  one  or  two  direct  clinical  observations 
that  are  of  interest  also.  Professor  Butcher,  of  the 
Pennsylvania  State  College,  has  performed  a  num- 
ber of  experiments  which  show  that  thyroxin,  the 
thyroid  hormone,  has  anti-neuritic  properties; 
which  means  that  it,  like  yeast,  for  example,  can 
cure  birds  suffering  from  polyneuritis, — a  disease 
first  shown  by  Funk  to  be  due  to  a  lack  of  one  of 
the  vitamines.2  If  this  is  so,  thyroxin  has  vitamine- 
like  characteristics. 

*See  the  author's  book,  Vitamines:  Essential  Food  Factors. 
New  York,  E.  P.  Button  &  Company,  1921. 

J  See  the  chapter  on  Beriberi  in  the  author's  book  on  Vitaminea. 


10        GLANDS  IN  HEALTH  AND  DISEASE 

Then  again,  McCarrison,  an  English  investiga- 
tor stationed  in  India,  has  shown  that  the  adrenal 
glands  of  birds  suffering  from  polyneuritis  are 
much  enlarged,  and  that  the  adrenaline  content  of 
these  glands  is  increased.  As  we  shall  see,  the 
adrenals,  like  the  thyroid,  are  glands  of  internal 
secretion,  and  adrenaline  is  the  active  hormone 
present  in  these  glands.  Even  more  remarkable 
is  his  discovery  that  though  the  adrenals  become 
enlarged,  the  other  ductless  glands  degenerate  and 
tend  to  disappear  altogether.  It  would  seem  as  if 
there  were  some  connecting  link  between  vitamine 
B  (the  vitamine  the  absence  of  which  causes  poly- 
neuritis)  and  adrenaline;  as  if  a  diet  containing 
adequate  amounts  of  vitamine  B  had  a  restraining 
influence  upon  the  output  of  the  adrenal  hormone. 

But  we  must  not  stretch  these  points  too  far, — 
at  least,  not  until  these  experiments  have  been  re- 
peated and  extended.  In  the  meantime  it  is  well  to 
point  out  some  obvious  differences,  if  only  to 
strengthen  our  judicial  attitude. 

Vitamines  are  very  susceptible  to  heat;  or  more 
accurately,  to  a  combination  of  heat  and  oxidation 
(exposure  to  air) ;  hormones  do  not  seem  to  be 
destroyed  at  a  temperature  even  of  boiling  water; 
at  least,  the  last  statement  is  true  of  secretin  (the 
intestinal  hormone)  and  one  or  two  others  that 
have  been  studied.  Then  again,  in  two  instances — 
adrenaline  (from  the  adrenal  gland)  and  thyroxin 


INTRODUCTORY  11 

(from  the  thyroid) — hormones  have  not  only  been 
isolated  in  the  pure  state,  but  they  have  actually 
been  synthesized  in  the  laboratory  from  relatively 
simple  compounds.  So  far,  not  only  have  we  been 
unable  to  synthesize  a  vitamine,  but  we  have  even 
been  baffled  in  our  attempts  to  isolate  one  in  a  pure 
condition. 

It  would,  perhaps,  be  more  in  harmony  with 
what  we  know  to  compare  hormones  with  amino- 
acids,  substances  that  are  obtained  when  the  pro- 
teins of  food  are  broken  up  by  the  enzymes  in  our 
digestive  system,  or  by  acids  used  in  the  chemist's 
laboratory.1  Chemically,  thyroxin  shows  striking 
relations  to  tryptophane;  and  adrenaline,  certain, 
though  not  such  striking  relations  to  tyrosine. 
Both  tyrosine  and  tryptophane  are  among  our  best- 
known  amino-acids. 

One  important  point  that  is  brought  out  in  a 
discussion  of  this  kind  is  to  emphasize  the  impor- 
tance of  the  "littlest  things."  Enzymes  (or  fer- 
ments), the  substances  that  act  on  our  food  in  the 
digestive  tract,  the  compounds  that  are  largely  re- 
sponsible for  much  of  the  metabolic  activity  of 
every  cell,  whether  plant  or  animal,  have  long 
been  known  to  illustrate  the  property  that  certain 
substances  possess,  of  bringing  about  chemical 
changes  in  a  large  quantity  of  material,  though  the 

'See  the   chapter   on  Ammo-Acida   in   the   author's   book  on 
Vitamines. 


12        GLANDS  IN  HEALTH  AND  DISEASE 

enzyme  present  may  be  there  in  relatively  small 
amount.  Still  more  remarkable  are  such  reactions 
in  that  the  enzymes  do  not  seem  to  undergo  any 
permanent  change :  at  the  end  of  the  reaction  we 
still  find  our  enzymes,  and  for  all  the  balance  tells 
us,  in  the  same  amounts  as  before  the  reaction. 

Substances  that  act  like  enzymes  are  called 
"catalysts."  A  catalyst  may  be  defined  as  a  sub- 
stance that  accelerates  a  chemical  reaction  without 
itself  undergoing  any  permanent  change.  Hor- 
mones and  vitamines  are  probably  catalysts. 

These  catalysts  are  not  confined  to  substances 
that  take  part  in  the  activities  of  the  living  organ- 
ism. The  best  method  for  the  manufacture  of  oil 
of  vitriol,  or  sulphuric  acid,  is  by  the  employment 
of  platinum  as  a  catalytic  agent :  provided  all  im- 
purities are  rigidly  excluded,  the  same  platinum 
can  be  used  over  and  over  again.  The  manufacture 
of  synthetic  ammonia  by  the  Haber  process  in- 
volves the  use  of  a  catalyst,  probably  nickel.  I  say 
"probably"  because  the  details  of  the  process  are 
carefully  guarded  as  trade  secrets.  At  any  rate, 
the  production  of  ammonia  from  the  nitrogen  of 
the  air,  and  the  hydrogen  that  can  be  obtained 
either  from  the  electrolysis  of  water,  or  as  a  by- 
product in  the  manufacture  of  lye,  can  be  brought 
about  with  the  help  of  a  catalytic  agent.  Since 
this  Haber  process  is  on  the  road  to  solving  the 
"nitrogen-fixation"  problem,  and  hence  many  of 


INTRODUCTORY  13 

our  fertilizer  difficulties,  the  catalyst  in  industry 
seems  destined  to  play  a  part  no  less  important 
than  the  catalyst  that  helps  to  maintain  the  chemi- 
cal equilibrium  of  the  body. 


CHAPTER  II 

THE  THYROID 

This  is  the  most  frequently  referred  to  of  the 
ductless  glands,  not  necessarily  because  it  is  the 
most  important,  but  because  much  of  the  history 
of  the  ductless  glands  centers  around  this  one ;  and 
also  because  of  the  success  that  has  attended  the 
treatment  of  at  least  one  form  of  thyroid  disease. 

The  thyroid,  which  usually  weighs  anywhere  be- 
tween one  and  two  ounces,  is  situated  -in  the  neck. 
It  consists  of  two  parts  on  either  side  of  the  larynx 
(organ  of  voice)  and  windpipe,  usually  con- 
nected by  a  narrow  strip  of  tissue.  In  contact 
with  the  thyroid  are  the  "parathyroids,"  still 
smaller  bodies,  which  were  for  a  long  time  not 
sharply  distinguished  from  the  thyroid  proper,  and 
which  as  a  consequence  gave  rise  to  much  confusion 
in  the  interpretation  of  experimental  results. 
These  parathyroids  will  receive  treatment  pres^ 
ently. 

That  the  thyroid  is  an  organ  that  plays  an  all- 
important  part  in  the  various  activities  of  the  body 
becomes  apparent  when  for  any  reason  it  behaves 

14 


THE  THYROID  15 

abnormally.  The  fluid,  or  still  better,  the  active 
hormone  that  the  body  secretes,  is  under  certain 
conditions  largely  increased.  We  get  then  a  con- 
dition of  hyper-thyroidism.  The  disease  known  as 
"exophthalmic  goiter"  (Graves's  disease  and  Base- 
dow's  disease  are  synonyms)  is  probably  a  case  in 
point.  On  the  other  hand,  a  condition  may  arise 
wherein  the  quantity  of  secretion  and  the  supply 
of  hormone  become  deficient.  This  may  develop 
"myxedema"  in  the  adult  and  "cretinism"  in  the 
infant;  such  being  examples  of  hypo-thyroidism. 
We  shalltake  these  up  in  turn,  and  we  shall  begin 
with  hypo-thyroidism. 

Eypothyroldlsm. — In  medicine  definite  clues  as 
to  the  type  of  disease  are  usually  obtained  by  pre- 
liminary experiments  with  animals.  We  find  that 
as  early  as  1859  Schiff,  a  Swiss  physiologist,  in- 
vestigated the  effect  of  thyroidectomy  on  animals 
( "thyroidectomy"  is  a  convenient  word  to  describe 
the  idea  of  the  surgical  removal  of  the  thyroid. 
"Dectomy"  is  derived  from  a  Greek  word  meaning 
"excision.")  His  results,  though  suggestive,  were 
inconclusive,  due  to  the  fact,  as  we  know  to-day, 
that  Schiff  removed  the  parathyroids  as  well  as 
the  thyroids.  But  this  physiologist  went  a  step 
further.  Having  removed  the  thyroid,  he  next  in- 
vestigated the  effect  of  implanting  thyroid  from  an 
animal  of  the  same  species.  The  results  in  a  num- 
ber of  cases  were  highly  encouraging. 


16        GLANDS  IN  HEALTH  AND  DISEASE 

Fired  by  the  work  of  the  English  physicians 
Gull  (1872)  and  Ord  (1878),  and  the  German 
Kocher  (1883),  Schiff,  in  1884,  published  his  cele- 
brated paper,  "On  the  Effects  of  the  Removal  of  the 
Thyroid  Body,"  in  one  of  the  Swiss  medical  jour- 
nals. How  clearly  Schiff  recognized  the  gland  to 
be  an  internal  secretory  one  may  be  gathered  from 
this  quotation:  "We  may  wonder  if  the  thyroid 
body  produces  in  its  interior  a  substance  which  it 
delivers  into  the  blood  stream  and  which  consti- 
tutes a  nutritive  element  for  another  organ  (ner- 
vous), or  whether  it  acts  mechanically  by  its  ana- 
tomical position.  To  decide  between  these  two 
alternatives,  it  is  necessary  to  find  a  means  of 
transplanting  it,  by  grafting  it  into  another  part 
of  the  body.  If,  after  this  has  been  done,  the  acci- 
dents resulting  from  its  removal  are  avoided  or  re- 
duced to  a  minimum,  it  is  evident  that  the  action 
of  the  thyroid  is  due  to  its  composition  and  not  to 
its  anatomical  relations ;  this  will  prove  the  thyroid 
to  have  a  chemical  function." 

The  grafts  Schiff  tried  disappeared  in  time,  but 
not  before  it  was  noticeable  that  there  was  an  im- 
provement in  the  condition  of  the  animal.  From 
these  results  he  concluded  that  "the  substance  of 
the  grafted  organ,  taken  up  by  the  blood,  serves 
to  counterbalance  the  untoward  effect  of  thyroi- 
dectomony" ; — clearly  a  case  of  hormonic  action. 

He  had  another  idea  which,  however,  he  did  not 


THE  THYROID  17 

put  to  the  test  of  experiment,  and  thereby  fell  short 
of  another  great  discovery :  "It  would  be  curious," 
he  writes,  "to  investigate  if  the  macerated  extract 
of  the  thyroid,  introduced  into  a  cavity,  or  injected 
into  the  rectum,  has  the  same  immunizing  power." 

A  repetition  of  Schiff's  experiments  by  other  in- 
vestigators did  not  always  corroborate  Schiff's 
findings.  We  have  already  suggested  that  an  in- 
complete knowledge  of  the  parathyroids  may  have 
been  the  cause  of  this.  We  may  also  add  that  not 
only  do  animals  of  different  species  behave  differ- 
ently, but  even  animals  of  the  same  species  do,  pro- 
vided there  is  a  marked  difference  in  age. 

Symptoms. — Where  the  operation  in  an  animal 
has  been  successfully  performed,  some  such  symp- 
toms as  the  following  develop:  The  skin  becomes 
thick  and  dry;  there  is  a  loss  of  hair;  the  animal 
shows  a  tendency  towards  obesity,  particularly  in 
certain  portions  of  the  body;  the  muscles  become 
weak  and  the  tissues  renew  themselves  but  slowly. 
The  blood  is  poor,  in  quality  and  quantity;  the 
temperature  is  below  normal ;  and  the  sexual  func- 
tions are  interfered  with.  This  interference  with 
the  sexual  glands  is  of  uncommon  interest,  since 
it  suggests  a  close  interrelationship  between  the 
various  hormones  of  the  body — an  observation  that 
is  strengthened  every  time  a  disease  due  to  a  hor- 
monic  disturbance  is  examined.  The  nervous  sys- 
tem is  also  attacked,  dullness  and  general  apathy 


18        GLANDS  IN  HEALTH  AND  DISEASE 

being  markedly  apparent.  A  histological  examina- 
tion shows  many  of  the  nerve  cells  to  have  shrunk 
in  size. 

Cretinism. — If  instead  of  removing  the  gland  it 
atrophies  or  wastes  away,  the  symptoms  are  quite 
identical.  In  a  child  where  such  a  condition  occurs 
we  find  growth  to  be  arrested.  The  head  and  face 
look  deformed;  the  expression  is  decidedly  idiotic. 
The  face  is  pale,  the  hair  thin,  the  skin  dry,  the 
abdomen  swollen.  The  development  of  the  genera- 
tive organs  is  delayed.  Deaf -mutism  is  quite  com- 
mon. These  are  all  symptoms  of  the  "cretinous" 
child,  the  disease  being  spoken  of  as  "cretinism." 

Professor  Falta  describes  a  cretinous  child,  four 
and  one-half  years  old,  as  follows :  "Head  at  birth 
already  large.  Speech  up  to  second  year  of  life 
consisted  of  the  simplest  words  only,  such  as  <tata/ 
'mama' ;  and  since  this  time  the  child  has  not  spoken 
much  otherwise.  Head  extremely  large.  Very  low 
forehead,  eyes  stand  wide  apart.  Saddle-nose; 
thick  broad  tongue  that  protrudes  from  the  mouth. 
Cheeks  very  thick,  throat  very  thick  and  stubby. 
Thyroid  not  palpable.  Thick  hair  on  back.  Skin 
of  the  body  springy,  elastic;  hands  and  fingers 
chubby.  Abdomen  much  distended.  The  child 
often  stares  into  space  for  a  long  time,  but  at  times 
is  lively  and  cries  loudly.  No  trace  of  speech. 
Puts  all  objects  into  his  mouth.  Impressions  of 


THE  THYROID  19 

hearing  entirely  absent ;  no  reactions  of  the  eyelids 
to  sounds." 

If  now  there  still  remains  some  question  as  to 
the  soundness  of  the  diagnosis,  all  doubts  are  im- 
mediately removed  by  prescribing  extracts  of  the 
thyroid  gland  to  the  young  sufferer.  The  recovery 
as  a  consequence  is  little  short  of  miraculous. 

Thyroid  feeding  and  the  development  of  frogs. — 
In  his  fascinating  article  on  "Natural  Death  and 
the  Duration  of  Life"  (Scientific  Monthly,  Decem- 
ber, 1919),  Professor  Jacques  Loeb  describes  the 
remarkable  effect  of  thyroid  feeding  on  the  devel- 
opment of  the  frog  and  salamander.  He  writes: 
"It  is  possible  that  some  of  the  changes  underlying 
metamorphosis  are  due  to  changes  in  the  circula- 
tion of  the  blood.  Gudernatsch  made  the  remark- 
able discovery  that  this  metamorphosis,  which  in 
our  climate  usually  occurs  during  the  third  or 
fourth  month  of  the  life  of  the  tadpole,  can  be 
brought  about  at  will  even  in  the  youngest  tadpoles 
by  feeding  them  with  thyroid  gland,  no  matter  from 
which  animal.  By  feeding  very  young  tadpoles 
with  this  substance,  frogs  not  larger  than  a  fly 
could  be  produced.  Allen  added  the  observation 
that  if  a  young  tadpole  is  deprived  of  its  thyroid 
gland,  it  is  unable  ever  to  become  a  frog ;  and  that 
it  remains  a  tadpole  which  can  reach,  however,  a 
long  life  and  continue  to  grow  beyond  the  usual  size 


20        GLANDS  IN  HEALTH  AND  DISEASE 

of  a  tadpole.  When,  however,  such  superannuated 
tadpoles  are  fed  with  thyroid  they  promptly  under- 
go metamorphosis. 

"These  observations  cleared  up  an  old  biological 
puzzle.  Salamanders  also  undergo  a  metamorpho- 
sis which  is,  however,  less  striking  than  that  of  the 
tadpole  of  a  frog.  In  the  salamander  the  meta- 
morphosis consists  chiefly  in  the  throwing  off  of 
the  gills,  and  in  changes  in  skin  and  tail.  In 
Mexico  a  salamander  occurs  which  through  its 
whole  life  maintains  its  tadpole  form,  namely,  the 
axolotl.  Attempts  to  induce  the  axolotl  to  meta- 
morphose failed  until  after  Gudernatsch's  discov- 
ery an  investigator  fed  the  axolotl  thyroid  gland, 
and  this  brought  about  metamorphosis.  ...  It 
seemed  possible  that  the  iodine  contained  in  the 
thyroid  was  the  active  principle  causing  metamor- 
phosis in  tadpoles.  This  was  confirmed  by  Swingle 
who  succeeded  in  inducing  metamorphosis  in  tad- 
poles by  feeding  them  with  traces  of  inorganic 
iodine." 

Administration  of  thyroid  extract. — Thyroid  ex- 
tract may  be  administered  in  one  of  three  ways: 
by  mouth,  by  injection  beneath  the  skin  (subcu- 
taneous), or  by  injection  into  a  vein  (intravenous). 
The  last  method  yields  the  quickest  response.  This 
might  be  expected  if  we  remember  that  the  thyroid 
hormone,  and  all  other  hormones,  reach  the  various 
parts  of  the  body  by  means  of  the  blood  stream. 


THE  THYKOID  21 

Usually,  however,  the  physician  prefers  to  mix  the 
thyroid  extract  with  the  patient's  food,  this  being 
a  much  simpler  proceeding,  and  in  the  long  run 
just  as  effective. 

Thyroid  gland  transplantation. — Why  when  the 
administration  of  thyroid  gland  is  so  efficacious, 
thyroid  gland  transplantations  should  be  under- 
taken to  cure  patients  suffering  from  hypothyroid- 
ism,  is  not  clear.  I  take  up  a  New  York  newspaper 
for  Dec.  9,  1920,  and  in  it  is  the  following  (special 
dispatch  from  Chicago)  :  "Mary  Zembok,  19,  of 
Joliet,  111.,  may  become  a  normal  girl  of  19 — that 
is  if  the  grafting  of  a  monkey  gland  into  her  neck 
to-day  restores  her  mentality  and  physical  develop- 
ment. Physicians  who  performed  the  operation 
said  that  it  had  been  successful.  Mary  had  been 
mentally  defective  almost  since  birth,  and  com- 
paratively paralyzed.  The  mother,  a  Pole,  has  five 
children  besides  Mary,  all  of  them  normal.  When 
Mary  was  two  years  old  it  became  apparent  that 
she  would  not  develop  into  a  normal  child,  and 
Mrs.  Zembok  relegated  her  to  the  basement  of  their 
home,  where  she  lived  in  perpetual  darkness  until 
two  months  ago,  when  the  health  authorities  learnt 
of  the  case.  The  child,  when  found,  was  immedi- 
ately removed  to  a  hospital  here.  It  was  decided 
that  the  only  hope  for  a  full  recovery  would  be  the 
gland  transplantation  operation.  To-day  the 
monkey,  a  full-grown  animal,  and  the  child  were 


22        GLANDS  IN  HEALTH  AND  DISEASE 

taken  to  the  operating  room,  the  thyroid  gland  re- 
moved from  the  animal  and  transplanted  into  the 
neck  of  the  child." 

I  submit  that  this  is  excellent  material  for  a 
novel,  play  or  "movie." 

As  I  write  this  paragraph  I  am  informed  that 
J.  R.  Brinkley,  M.D.,  C.M.,  Se.D.,  Chief  Surgeon, 
Brinkley-Jones  Hospital  and  Training  School  for 
Nurses,  Milford,  Kansas,  graduate  of  the  medical 
department  of  Loyola  University,  who  has  travelled 
"all  over  the  world" — that  this  same  doctor  has 
completed  a  96-page  book  on  the  Goat  Gland  Trans- 
plantation. Dr.  Van  Buren,  reviewing  the  book 
for  the  New  York  Times,  says :  "A  fair  commen- 
tary on  this  book,  I  should  say,  is  that  one  of  its 
outstanding  features  is  its  delightful  naivete." 

Is  the  absence  of  hormone  responsible  for  cre- 
tinism?— The  very  fact  that  administration  of  thy- 
roid extract  causes  recovery  in  the  case  of  cretin- 
ism, a  specific  disease,  points  to  the  presence  of 
some  hormone  in  the  thyroid  that  is  responsible — 
some  substance,  then,  that  reaches  the  other  organs 
of  the  body  by  means  of  the  blood  stream.  Unfor- 
tunately for  the  welfare  of  the  community,  the 
other  ductless  glands  do  not  exhibit  this  specificity 
to  the  same  marked  degree.  With  them  the  situa- 
tion that  arises  is  often  of  a  character  so  compli- 
cated as  to  baffle  the  sharpest  intellects  of  the 
medical  profession. 


THE  THYROID  23 

Myaedema. — The  atrophy  of  the  thyroid  in  the 
adult  gives  rise  to  a  condition  quite  similar  to  that 
described  in  the  child.  Here,  however,  instead  of 
calling  the  disease  "cretinism''  we  call  it  "myxe- 
dema,"  to  denote  the  mucous  fluid  that  gathers  be- 
neath the  tissues  and  that  gives  rise  to  swellings 
all  over  the  body.  There  is  a  belief  that  the 
immediate  cause  of  this  disease  is  due  to  the  pres- 
ence of  an  excess  of  "mucin,"  a  substance  that  gives 
the  "ropy"  consistency  to  saliva,  and  that  is  also 
found  in  various  parts  of  the  body.  The  thyroid 
hormone  presumably  prevents  the  accumulation 
of  an  excess  of  mucin. 

Symptoms  in  myxedema. — A  person  afflicted 
with  myxedema,  which,  by  the  way,  is  more  com- 
mon in  woman  than  in  man  in  the  proportion  of  at 
least  two  to  one,  gradually  assumes  an  appearance 
that  is  beyond  all  recognition.  The  dull  mind,  the 
sluggish  movement,  the  unsteady  gait,  combine 
with  the  general  alteration  of  features  to  make  the 
person  a  most  pitiable  spectacle.  The  patient  may 
eat  quite  little,  yet  so  poor  is  the  assimilatory 
mechanism,  that  even  that  little  is  not  easily  taken 
care  of ;  so  that  there  is  a  marked  accumulation  of 
food  reserve  in  the  body,  and  the  individual  be- 
comes abnormally  fat. 

Treatment  with  thyroid  extract. — Here  again, 
as  with  the  child,  cures  may  be  obtained  by  the  ad- 
ministration of  thyroid  extract.  But  in  both  cases 


24        GLANDS  IN  HEALTH  AND  DISEASE 

the  extract  must  be  administered  at  regular  inter- 
vals and  kept  up  indefinitely,  otherwise  there  is  a 
relapse.  The  discordant  results  that  have  been 
reported  with  thyroid  feeding  in  myxedema  are 
almost  invariably  due  to  the  type  of  thyroid  extract 
used.  The  various  samples  of  these  on  the  market 
vary  greatly  in  efficacy,  due  no  doubt  to  the  method 
and  source  of  extraction.  Two  commercial  houses 
justly  famous  for  the  preparation  of  such  extracts 
are  Burroughs  Wellcome,  of  London,  and  Parke, 
Davis,  of  Detroit,  Mich.  Now  that  Kendall  has 
succeeded  in  isolating  the  active  principle  of  the 
thyroid,  there  need  be  little  occasion  for  future 
variation. 

Evidently  the  administration  of  the  thyroid  sub- 
stance does  not  give  rise  to  any  accumulation  of 
the  material  in  the  system.  A  certain  amount  is, 
as  it  were,  used  up  in  each  operation.  Under  nor- 
mal conditions,  when  the  gland  in  the  body  func- 
tions properly,  the  amount  of  hormone  necessary 
for  regulating  metabolic  processes  and  nerve  re- 
sponses is  manufactured  whenever  required.  This, 
of  course,  is  no  longer  possible  when  the  gland  is  in 
an  atrophied  condition. 

Many  cases  are  on  record  which  show  the  de- 
velopment of  myxedema  when  the  thyroid  is  re- 
moved— removed  because,  let  us  say,  of  a  tumor 
growth.  Both  the  removal  of  the  thyroid  and  the 
atrophy  of  this  organ  give  rise  to  the  same  disease. 


THE  THYKOID  2S 

A  number  of  investigators — among  them  the  justly 
famous  Mayo  brothers  of  Rochester — showed  that 
where  surgical  removal  of  the  thyroid  becomes  im- 
perative, myxedema  may  be  prevented  by  leaving 
intact  at  least  one-fourth  of  the  organ. 

Iodine  in  the  thyroid. — It  would  have  been 
strange  if  no  attempts  had  been  made  to  isolate 
the  hormone  or  active  principle  present  in  the  thy- 
roid gland.  As  a  matter  of  fact,  many  such  at- 
tempts were  made,  particularly  after  the  success- 
ful isolation  of  the  active  principle  of  the  adrenal 
glands.  The  first  important  discovery  that  was 
made  in  this  direction  was  by  Baumann  in  1895, 
who  showed  that  the  thyroid  is  rich  in  the  element 
iodine.  Until  Baumann's  time  no  one  had  had  the 
slightest  suspicion  that  such  an  element  as  iodine 
existed  in  the  body;  yet  a  careful  analysis  of  the 
thyroid  showed  it  to  be  there  in  appreciable  quan- 
tity. That  naturally  suggested  two  things:  that 
the  active  principle  of  the  gland  was  an  iodine  com- 
pound, and  that  iodine,  or  more  likely  foods  con- 
taining iodine,  have  to  be  supplied  to  the  body. 

Isolation  of  the  thyroid  hormone. — Much  work 
has  since  been  done  on  the  chemistry  of  the  iodine 
compound  in  the  gland.  Various  substances  have 
been  isolated  from  it  containing  percentages  of 
iodine  greater  than  that  in  the  whole  gland,  show- 
ing that  the  preparations,  if  not  pure,  did  at  least 
represent  concentrated  fractions.  These  sub- 


26        GLANDS  IN  HEALTH  AND  DISEASE 

stances  were  given  various  names,  and  their  dis- 
coverers claimed  that  their  iodine  compounds  could 
do  all  that  the  gland  extract  itself  could  do :  that, 
in  short,  such  substances  could  be  employed  in  the 
place  of  the  gland  extract  in  the  treatment  of  cre- 
tinism and  myxedema.  Many  have  been  the  state- 
ments for  and  against  the  use  of  such  preparations. 
Lately,  however,  E.  C.  Kendall,  working  at  the 
newly-created  Mayo  Foundation  in  Rochester,  has, 
after  some  ten  years  of  intensive  work,  actually 
succeeded  in  isolating  the  iodine  compound  in  a 
pure  form.  He  calls  it  "thyroxin,"  and  the  com- 
pound contains  no  less  than  60  per  cent,  of  iodine. 
It  has  already  been  extensively  used  by  Kendall 
and  others  in  the  treatment  of  thyroid  deficiency 
diseases,  with  marked  success  in  almost  all  cases. 
"This  could  be  made  even  stronger,  as  we  have 
not  found  a  single  case  of  thyroid  deficiency  that 
has  not  responded  to  an  intravenous  injection  of 
thyroxin ;  and,  furthermore,  the  response  is  a  quan- 
titative one.  That  is,  for  every  milligram  (one- 
thousandth  of  one  gram,  and  2%  grams  correspond 
to  one  ounce)  injected,  the  basal  metabolic  rate 
(see  p.  39)  increases  2~y2  per  cent."  (E.  C.  Ken- 
dall.) This  constitutes  another  triumph  for  the 
chemist  in  his  application  of  chemistry  to  medi- 
cine.1 

1  Kendall's  work.    This  work  of  Kendall's  is  of  such  importance 
that  it  warrants  further  discussion.     As,  however,  some  knowl- 


THE  THYEOID  27 

Endemic  goiter. — Before  dismissing  the  subject 
of  hyposecretion  a  word  must  be  said  about  the 
cases  known  as  endemic  goiter.  In  such  cases  the 
front  part  of  the  neck  becomes  swollen,  due  to  the 
enlargement  of  the  thyroid  gland  (hence  the  name 

edge  of  chemistry  must  be  assumed  at  this  point,  I  would  suggest 
that  those  readers  who  do  not  possess  such  knowledge  had 
better  skip  this  footnote. 

The  first  detailed  account  of  the  isolation  of  the  active  prin- 
ciple appeared  in  1919,  when  Kendall  published  his  paper,  "On 
the  Isolation  of  the  Iodine  Compound  Which  Occurs  in  the 
Thyroid,"  in  the  Journal  of  Biological  Chemistry.  The  research 
was  begun  in  1910,  so  that  no  less  than  nine  years  of  continuous 
work  were  spent  in  attempts  to  isolate  the  hormone.  Up  to  1919, 
33  grams  (a  little  over  an  ounce)  of  the  hormone  "thyroxin"  had 
been  isolated  from  6.550  pounds  of  fresh  thyroid. 

Kendall's  method  of  isolating  thyroxin  is  as  follows:  Fresh 
thyroid  gland  is  hydrolized  with  sodium  hydroxide.  The  fats 
are  removed  by  rendering  the  sodium  soaps  insoluble,  and  the 
clear  alkaline  filtrate  is  acidified.  Acid  soluble  and  acid  insoluble 
portions  are  obtained,  each  containing  one-half  of  the  total 
iodine.  (Kendall  has  confined  his  attention  to  the  acid-insoluble 
portion,  which  contains  all  the  thyroxin,  but  what  type  of 
iodine  compound  is  in  the  acid  soluble  portion,  and  to  what 
extent  that  iodine  combination  is  of  importance,  remains  to  be 
seen.)  The  acid  insoluble  portion  is  filtered  off,  the  precipitate 
redissolved  in  sodium  hydroxide  and  reprecipitated  with  hydro- 
chloric acid.  The  substance  is  next  air-dried  and  dissolved  in  95 
per  cent,  alcohol.  A  hot,  concentrated,  aqueous  solution  of  barium 
hydroxide  is  added  to  the  alcoholic  filtrate,  and  the  mixture 
heated  under  a  reflux  condenser.  This  is  next  filtered,  a  small 
amount  of  sodium  hydroxide  added  to  the  filtrate,  and  carbon 
dioxide  passed  through  the  solution.  Barium  and  sodium  car- 
bonates are  removed  by  filtration,  and  the  alcohol  is  removed  by 
distillation. 

The  product  is  purified  by  redissolving  in  alcoholic  sodium 
hydroxide  and  again  passing  in  carbon  dioxide.  The  sodium  car- 
bonate is  filtered,  and  the  alcohol  evaporated.  The  last  traces  of 
alcohol  are  removed  by  heating  on  a  water  bath.  At  this  point 
the  monosodium  salt  of  thyroxin  separates.  The  thyroxin  itself 
is  obtained  by  dissolving  the  salt  in  alcoholic  alkali,  and  pre- 
cipitating with  acetic  acid. 


28         GLANDS  IN  HEALTH  AND  DISEASE 

"goiter"),  and  a  pressure  is  exerted  on  neighbor- 
ing glands  such  as  the  trachea  and  esophagus.  The 
enlargement  of  the  thyroid  gland  would  lead  one 
to  suspect  that  there  is  a  hyper-,  rather  than  a  hypo- 
secretion  of  the  hormone.  This,  however,  is  not 
true  of  this  type  of  goiter,  which  is  quite  prevalent 
in  Switzerland,  and  in  the  Lake  sections  of  our 
country  (hence  called  "endemic"  to  denote  its  local 
character) .  That  we  here  deal  with  a  type  of  hypo- 
secretion  is  made  evident  by  the  general  symptoms 

Thyroxin  is  4,5,6  tri-hydro-4,5,6  tri-iodo-2-oxy-beta  indolepro- 
pionic  acid 
I          H 


V 


H     H  0 

c-J-A-o' 

OH 


It  is  a  colorless,  odorless,  crystalline  substance,  insoluble  in 
aqueous  solutions  of  all  acids,  including  carbonic;  soluble  in 
sodium,  potassium  and  ammonium  hydroxides;  slightly  soluble 
in  sodium  and  potassium  carbonates.  It  forms  salts  with  metals 
and  acids.  It  contains  65  per  cent,  of  iodine. 

The  above  formula  was  established  by  an  analysis  of  the  sub- 
stance, and  by  a  study  of  its  derivatives. 

An  interesting  observation,  made  by  Dr.  Dutcher,  but  not  yet 
confirmed,  so  far  as  I  am  aware,  is  to  the  effect  that  thyroxin 
has  vitamine  properties;  it  behaves  like  yeast,  for  example,  in 
curing  birds  of  polyneuritis  and  men  of  beriberi  (see  the  chapter 
on  Beriberi  in  the  author's  book  on  Vitamines).  Are  we  after 
all  on  the  eve  of  discovering  some  relationship  between  vitamines 
and  hormones? 


THE  THYROID  29 

that  develop,  and  by  the  ready  response  to  treat- 
ment with  thyroid  extract.  Poultices  of  burnt  sea- 
weed— a  fruitful  source  of  iodine — and  iodine  itself 
painted  on  the  skin,  were  used  for  this  disease  long 
before  it  was  known  that  the  thyroid  contained  this 
element. 

Iodine  an  essential  element. — Now  as  to  the  io- 
dine itself,  is  it  really  essential  to  the  body?  An 
element  can  neither  be  synthesized  in  the  labora- 
tory nor  in  the  body ;  it  can  merely  be  obtained  from 
nature  or  from  compounds  that  already  contain  it. 
If  we  deprive  our  food  of  all  iodine  we  deprive  the 
thyroid  of  what  seems  to  be  its  essential  element. 
Yet  the  situation  is  not  as  clear  as  it  seems;  for 
though  many  experiments  have  shown  that  thyroid 
activity  and  the  iodine  content  of  the  gland  go  hand 
in  hand,  yet  cases  are  known — of  animals,  it  is 
true — where  the  thyroid  contains  no  iodine  at  all, 
and  yet  the  animal  seems  quite  normal.  On  the 
other  hand,  in  endemic  goiter  some  remarkable 
cures  have  been  obtained  by  the  administration  of 
simple  inorganic  iodides.  Marine  and  Kimball,  of 
the  Western  Keserve  University,  Cleveland,  started 
in  1917  with  a  survey  of  the  incidents  and  types  of 
thyroid  enlargement  in  the  schoolgirls  of  Akron, 
Ohio,  from  the  fifth  to  the  twelfth  grades  inclusive. 
For  treatment  they  used  sodium  iodide,  which  was 
taken  in  doses  of  three  grains  daily  for  ten  consecu- 
tive school  days,  repeated  each  spring  and  autumn. 


30        GLANDS  IN  HEALTH  AND  DISEASE 

Becently  (June,  1920)  they  published  results  of 
studies  which  covered  a  period  of  some  thirty 
months.  Of  2,190  pupils  that  had  received  the 
sodium  iodide  treatment,  five  had  shown  enlarge- 
ment of  the  thyroid,  while  of  2,305  pupils  who  had 
not  received  any  such  treatment,  495  showed  an 
enlarged  thyroid. 

In  a  later  article  (Oct.  1,  1921)  they  write:  "Of 
1,182  pupils  with  thyroid  enlargement  at  the  first 
examination  who  took  the  prophylactic,  773  thy- 
roids have  decreased  in  size ;  while  of  1,048  pupils 
with  thyroid  enlargement  at  the  first  examination 
who  did  not  take  the  prophylactic,  145  have  de- 
creased in  size.  .  .  Klinger  has  recently  (1921) 
reported  even  more  striking  curative  results  in  the 
school  children  of  the  Zurich  district.  He  worked 
with  school  populations  in  which  the  incidents  of 
goiter  varied  from  82  to  95  per  cent.,  while  our 
maximum  incidence  in  Akron  was  56  per  cent. 
With  such  a  high  natural  incidence  of  goiter,  his 
observations  naturally  deal  more  with  the  curative 
effects.  Thus  of  760  children,  90  per  cent,  were 
goitrous  at  the  first  examination.  After  fifteen 
months'  treatment  with  iodine,  only  28.3  per  cent, 
were  goitrous,  of  a  total  of  643  children  re-ex- 
amined." 

Hypersecretion. — An  excessive  secretion  (hy- 
persecretion)  developed  by  the  thyroid  gland  may 
give  rise  to  the  disease  commonly  known  as  "ex- 


THE  THYROID  31 

ophthalmic  goiter/'  though  the  English  sometimes 
call  it  "Graves's  disease,"  and  the  Germans,  "Base- 
dow'sche  Krankheit,"  to  denote  the  work  done  by 
pioneers.  Often  these  diseases  present  a  greater 
complexity  than  a  mere  hypersecretion.  Here 
again  much  of  the  preliminary  work  was  done  by 
experiments  on  animals.  Instead,  however,  of  re- 
moving the  thyroid  gland — which  we  do  when  we 
study  the  effects  of  hyposecretion — extra  doses  of 
extracts  of  the  gland  are  administered.  When  this 
is  done  we  almost  invariably  produce  symptoms  in 
the  animal  that  bear  a  strong  resemblance  to  ex- 
ophthalmic goiter  in  man. 

Symptoms  in  exophthalmic  goiter. — As  might  be 
suspected,  the  symptoms  of  this  disease  are  very 
much  the  reverse  of  those  in  cretinism  and  myxe- 
clema.  The  slowing  up  of  cellular  processes,  so 
characteristic  of  myxedema  sufferers,  gives  place 
to  a  decided  acceleration  of  these  processes.  The 
stupid,  apathetic  expression  is  replaced  by  an  anx- 
ious, restless  one.  In  the  place  of  a  deposit  of  fat 
there  is  a  wasting  away  of  the  tissues.  The  subject 
becomes  thin  because  of  excessive  metabolism  (we 
shall  take  up  the  question  of  metabolism  later). 
The  pulse  is  rapid — it  may  vary  from  100  to  140 
per  minute — and  irregular.  The  thyroid  is  usually, 
though  not  invariably,  increased  in  size  (hence 
"goiter").  There  is  also  usually,  though  not  in- 
variably, an  abnormal  protrusion  of  the  eyeball 


32         GLANDS  IN  HEALTH  AND  DISEASE 

(hence  the  name  "exophthalmos," )  giving  the  sub- 
ject a  "startled"  expression ;  and  this  goes  hand  in 
hand  with  his  anxious,  restless  appearance.  Very 
often  the  patient  suffers  from  profuse  perspiration. 

The  Komans  were  evidently  not  unfamiliar  with 
this  disease,  for  it  is  stated  that  they  refused  to 
buy  a  slave  if  he  had  an  enlarged  goiter,  or  if  he 
showed  protruding  eyeballs,  on  the  very  practical 
grounds  that  he  was  not  a  fit  subject  for  hard 
work. 

One  or  more  of  the  symptoms  enumerated  show 
themselves  in  the  individual  suffering  from  exoph- 
thalmic goiter;  but  one  symptom  that  is  always 
present  and  that,  so  to  speak,  gives  the  clue  to  the 
type  of  disease,  is  the  excessive  rapidity  in  the 
action  of  the  heart  (tachycardia). 

Not  distantly  related  to  the  physical  condition 
of  the  patient  is  his  mental  state.  The  relation  of 
the  ductless  glands  to  the  general  mental  make-up 
of  the  individual  is  of  sufficient  importance  to  war- 
rant special  treatment,  and  a  chapter  will  be  de- 
voted to  that  subject  later  on.  Here  it  may  be 
mentioned  that  the  patient  suffering  from  exoph- 
thalmic goiter  becomes,  as  Dr.  Cobb  puts  it,  an 
^intractable,  selfishj__restless  and  inconsiderate 
being.  The  medical  attendant  as  a  rule~receives 
the  full  benefit  of  this,  and  can  do  little  that  is 
right.  He  is  either  old-fashioned  when  he  explains 
that  the  reason  for  rest  in  bed,  for  example,  is  to 


THE  THYROID  33 

avoid  straining  an  already  weakened  heart;  or  an 
ignoramus  if  he  insists  that  the  rest  combined 
with  hygienic  principles  offers  the  best  hope  for 
alleviating  the  disease.  If  he  suggests  trying  a  new 
remedy  he  is  experimenting  with  her ;  if  he  persists 
with  the  old  he  is  a  'stick-in-the-mud.' " 

Dr.  Cobb  in  his  example  deliberately  uses  the 
feminine  gender  because  the  disease  is  really  far 
more  common  in  the  female  than  in  the  male.  The 
proportion  is  placed  by  some  authorities  as  high 
as  five  to  one.  An  attempted  explanation  for  this 
"partiality"  is  based  on  the  fact  that  in  the  female 
the  gland  is  enlarged  usually  at  puberty  and  dur- 
ing pregnancy. 

Treatment. — When  we  come  to  the  means  at  our 
disposal  in  bringing  about  a  cure,  we  find  no  such 
definite  road  to  success  as  in  cases  of  hypothyroid- 
ism.  There,  as  will  be  remembered,  definite 
amounts  of  extracts  of  the  thyroid  gland,  when 
regularly  administered,  changed  the  secretion  of 
the  gland  from  subnormal  to  that  approaching  nor- 
mal. Here,  with  an  excessive  secretion,  it  might 
be  surmised  that  a  partial  removal  of  the  gland 
would  be  successful  in  restoring  the  health  of  the 
sufferer.  This  has  been  tried  many  times,  and 
with  success  in  a  fair  number  of  cases.  But  the 
operation  is  a  difficult  one,  and  only  a  surgeon 
of  extraordinary  skill  and  much  experience  can 
perform  it;  and  even  then  a  successful  operation 


34        GLANDS  IN  HEALTH  AND  DISEASE 

is  often  followed  by  post-operative  changes  that 
are  quite  discouraging — a  factor  that  of  course 
enters  into  many  other  types  of  operations.  In 
any  case,  unless  the  disease  has  taken  a  very  grave 
turn,  when  the  individual  is  pretty  much  on  the 
borderland  between  life  and  death,  the  treatment 
is  apt  to  be  anything  but  surgical. 

Treatment  other  than  surgical  centers  around 
the  word  "rest."  No  particular  insight  on  the  part 
of  the  lay  reader  is  required  to  understand  the 
reason  for  this.  If  the  body  machine  is  perform- 
ing its  cycle  of  operations  at  an  accelerated  speed, 
anything  that  will  tend  to  decrease  the  rate  will 
prove  beneficial.  Dr.  Charles  Mayo  says:  "The 
opinion  of  an  eminent  surgeon  (Kocher)  that  90 
per  cent,  of  all  goiters  can  be  improved  so  as  to 
make  operations  unnecessary,  was  probably  based 
upon  observations  of  the  effect  of  rest,  for  rest  is 
the  common  element  in  all  the  various  forms  of 
treatment  that  have  proved  successful." 

The  attending  physician  has,  of  course,  to  con- 
sider the  question  of  diet  and  the  use  of  drugs. 
Food  containing  iodine  should,  ipso  facto,  be  barred 
from  the  table,  on  the  assumption  that  since  the 
hormone  responsible  for  thyroid  activity  is  prob- 
ably an  iodine  compound,  we  need  do  nothing  to 
increase  the  quantity  of  iodine  in  the  body.  Then 
again  a  drug  that  will  tend  to  decrease  the  rapid 
action  of  the  heart  may  prove  advisable.  These 


THE  THYKOID  35 

items  can  be  safely  left  to  the  discretion  of  the 
medical  adviser. 

So  far  attempts  to  find  some  direct  and  simple 
cure  for  exophthalmic  goiter  have  failed.  The 
"rest"  cure  in  many  cases,  and  removal  of  part  of 
the  gland  in  a  number  of  cases,  have  proved  suc- 
cessful. 'Other  methods  of  "cure"  include  the  pro- 
duction of  a  substance  that  will  act  as  an  anti- 
toxin, and  neutralize  the  excessive  quantity  of 
hormone  present;  the  application  of  X-rays;  and 
the  administration  of  extracts  of  parathyroids  or 
the  thymus  gland,  or  of  calcium  salts. 

It  may  not  be  amiss  to  point  out  at  this  time 
that  the  psychic  factor  in  the  treatment  of  hyper- 
thyroidism  cannot  be  overlooked.  Psycho-analysis, 
handled  by  pseudo-scientists,  has  become  a  laugh- 
ing stock,  just  as  glandular  treatment  and  the  gen- 
eral subject  of  the  ductless  glands  threatens  to 
become ;  but  psycho-therapy,  practised  by  the  skill- 
ful physician,  is  at  times  of  inestimable  aid  in  put- 
ting the  patient  on  his  feet. 

Metabolism  studies. — Cases  of  hyper-  and  hypo- 
thyroidism  have  fairly  well-recognizable  symptoms. 
These  have  already  been  discussed.  But  we  have 
to  describe  a  method  which  helps  the  diagnosis  a 
great  deal.  This  depends  upon  the  fact  that  the 
thyroid  is  par  excellence  the  organ  that  regulates 
the  metabolism  of  the  body. 

But  before  we  go  any  further  we  must  explain 


36         GLANDS  IN  HEALTH  AND  DISEASE 

what  we  mean  by  the  word  "metabolism."  Food 
is  taken  into  the  system,  and  with  the  help  of 
enzymes  or  ferments  and  the  oxygen  of  the  air, 
undergoes  chemical  changes  in  the  body,  yielding 
carbon  dioxide,  moisture,  and  various  nitrogenous 
products  that  are  eliminated  principally  through 
the  kidneys.  The  processes  involved  are  digestion, 
assimilation  and  excretion.  Under  the  heading 
of  metabolism  we  may  include  all  those  changes 
that  occur  in  foodstuffs  from  the  time  they  are 
absorbed  to  the  time  they  are  excreted.  Huxley 
used  the  word  "metabolism"  to  "denote  the  sum 
total  of  those  chemical  changes  which  take  place 
in  living  matter,  and  in  virtue  of  which  we  speak 
of  it  as  living"  (metabolism  comes  from  the  Greek 
meaning  "change.") 

Lavoisier. — Lavoisier,  a  Frenchman,  more  than 
a  hundred  years  ago  showed  that  valuable  infor- 
mation as  to  the  metabolic  changes  that  go  on  in 
the  body  can  be  obtained  in  one  of  three  ways: 
by  estimating  the  amount  of  oxygen  consumed,  or 
of  carbon  dioxide  eliminated,  or  of  heat  evolved. 
With  regard  to  the  heat  evolved,  it  must  be  remem- 
bered that  the  reactions  of  the  body,  like  all  chemi- 
cal reactions,  are  accompanied  by  temperature 
changes — usually  by  an  increase  of  temperature, 
as  in  the  case  of  the  body. 

Since  Lavoisier's  time,  chemists  and  physiologists 


THE  THYROID  37 

have  given  much  attention  to  the  study  of  "respira- 
tory exchange" — to  the  relationship  of  oxygen  in- 
take and  carbon  dioxide  output, — and  to  the  meas- 
urement of  the  heat  evolved  in  the  reaction.  Vari- 
ous types  of  calorimeters  have  been  invented  for 
that  purpose.1  In  Germany,  Voit,  Pettenkofer, 
Kubner  and  Zuntz,  and  in  this  country,  Atwater,- 
Eosa  and  Benedict,  have  done  much  to  advance  our 
knowledge  in  this  direction.  The  sum  of  such 
knowledge  has  been  to  supply  us  with  exact  data 
regarding  the  heat  evolved  in  individuals  under 
varying  conditions.  If  a  certain  amount  of  heat 
is  evolved,  that  amount  of  heat  must  also  be  sup- 
plied, and  the  supply  of  such  heat  can  come  only 
from  the  food  supplied  and  "burnt"  in  the  body. 
That  is  how  we  arrive  at  certain  fundamental  food 
requirements. 

Constant  Temperature. — Not  the  least  remark- 
able of  the  many  remarkable  phenomena  noticeable 
when  we  study  the  living  organism  is  the  way  the 
temperature  within  us  remains  constant.  The 
temperature  outside  may  vary  considerably,  yet 
under  normal  conditions  the  temperature  within 
us  varies  very  little.  A  constant  temperature 
means  a  constant  heat  production. 

Of  course  this  is  true  only  of  warm-blooded  ani- 
mals, not  of  cold-blooded  ones,  such  as  the  frog; 

1  See  the  chapter  on  Calories  in  the  author's  book  on  Vitamines. 


38        OLANDS  IN  HEALTH  AND  DISEASE 

its  temperature  is  but  slightly  higher  than  that  of 
its  environment,  and  its  metabolism,  therefore, 
varies  considerably  from  winter  to  summer. 

Surface  area. — Though  for  a  long  time  the  metab- 
olism (measured  in  calories)  of  man  and  warm- 
blooded animals  was  taken  to  be  proportional  to 
their  weight,  Eubner,  of  the  University  of  Berlin, 
has  shown  that  a  closer  relationship  is  obtained  if 
instead  of  the  weight  we  substitute  the  surface  area 
of  the  man  or  animal — that  is  to  say,  the  area  of 
the  surface  exposed.  Then  we  get  such  figures  as 
the  following: 

Calories  produced 

A 

Per  square 

Per  kilo          meter  of 
surface 

Weight  in  kilograms 
(1  kilo  equals  2%  pounds) 

Horse    441  11.3  948 

Pig    128  19.1  1078 

Man    64.3  32.8  1042 

Dog     15.2  51.5  1039 

Goose    3.5  66.7  969 

Mouse    0.018  212.0  1188 

(A  calorie  is  the  amount  of  heat  necessary  to  raise  one  kilo  of 
water  one  degree  centigrade.  A  meter  is  a  little  over  a  yard.) 

Making  allowances  for  experimental  difficulties 
and  inaccuracies,  the  last  column  of  figures  is  fairly 
constant,  unlike  the  second,  which  varies  consider- 
ably. We  may  say  then  that  there  is  an  evenness  of 
heat  production  per  unit  of  body  surface. 

The  difficulty  in  referring  to  surface  area  is  a 


THE  THYEOID  39 

difficulty  connected  with  measuring  such  an  area. 
Mathematicians  have  not  been  wanting  to  devise 
a  formula  which  connects  weight  with  surface  area. 
All  you  have  to  do  is  to  weigh  your  man  and  then 
multiply  the  cube  root  of  the  body  weight  squared 
by  12.3,  and  you  have  your  surface  area !  Du  Bois, 
however,  working  at  the  Kussell  Sage  Institute  of 
Pathology,  connected  with  the  Bellevue  Hospital, 
New  York,  has  shown  a  method  by  which  the  sur- 
face area  can  actually  be  measured.  "He  covered 
the  body  surface  with  light-fitting  underwear,  ap- 
plied melted  paraffin,  and  then  paper  strips  to 
prevent  change  in  area  when  the  covering  was  re- 
moved. This  model  of  the  surface  when  cut  into 
flat  pieces  was  photographed  upon  paper  in  which 
equal  areas  were  of  equal  weight.  From  the  weight 
of  paper  which  received  the  photographic  impres- 
sion the  area  of  body  surface  could  be  calculated."  * 
So  accurate  is  this  method,  that  a  ball  having  an 
area  of  0.1490  square  meter,  when  measured  in 
this  way,  gave  the  figure  0.1488.  Du  Bois  also 
showed  that  the  calculation  of  surface  area  by  the 
formula  method  involved  an  average  inaccuracy 
of  16  per  cent. 

Basal  Metabolism. — Using  the  Du  Bois  method, 
the  heat  production  per  square  meter  of  surface  is 
39.7  calories  per  hour,  provided  the  individual  is 
resting  and  is  "normal,"  and  provided  the  experi- 

aLusk,  The  Science  of  Nutrition,  p.  214. 


40        GLANDS  IN  HEALTH  AND  DISEASE 

merit  is  carried  out  before  the  administration  of 
food  in  the  morning  (that  is,  after  he  has  fasted 
for  12  to  14  hours).  This  is  the  so-called  "basal 
metabolism,"  and  constitutes  the  unit  of  reference 
whereby  we  can  measure  what  are  the  deviations 
from  the  normal. 

Metabolism  in  thyroid  disease. — All  this  is  a 
long,  but,  I  believe,  a  necessary  preface  to  what  we 
are  now  coming  to :  metabolism  in  thyroid  disease. 
We  started  out  by  saying  that  the  thyroid,  by 
means  of  its  hormone,  regulates,  perhaps  more  than 
any  other  organ  of  the  body,  the  amount  of  metab- 
olism in  the  body.  Under  normal  conditions,  with 
a  normal  thyroid,  the  metabolism  of  the  individual 
is  such  as  to  show  a  normal  abasal  metabolism." 
When,  however,  hyper-thyroidism  sets  in,  with  a 
gland  that  is  excessively  active,  the  rise  in  metab- 
olism above  the  normal  amount  is  considerable. 
Vice  versa,  where  the  patient  suffers  from  hypo- 
thyroidism,  with  a  decreased  activity  of  the  thy- 
roid, there  is  a  decided  drop  in  the  metabolic  rate. 
For  example,  when  the  metabolism  of  a  patient 
suffering  from  exophthalmic  goiter  (hyper-thyroid- 
ism)  was  investigated  it  was  shown  to  be  75  per 
cent,  above  the  normal  basal  of  39.7  calories  (usu- 
ally written  +75)  ;  on  the  other  hand,  with  a  cretin 
the  metabolism  was  22  per  cent,  below  normal 
( — 22).  Incidentally  the  same  cretin,  after  being 


THE  THYEOID  41 

fed  with  thyroid  extract,  showed  a  normal  basal 
metabolism. 

Value  of  basal  metabolic  studies. — Of  what  value 
are  these  metabolic  studies?  Of  the  very  highest 
in  thyroid  disease;  for,  taken  together  with  the 
other  symptoms,  a  metabolism  experiment  will 
confirm  or  disprove  the  diagnosis.  But  there  is 
a  still  more  important  point  to  be  brought  out: 
once  the  diagnosis  has  been  made  and  a  method  of 
treatment  adopted,  its  progress  can  be  followed  by 
periodically  carrying  out  such  metabolic  experi- 
ments. If  the  patient  suffers  from  hyper-thyroi- 
dism,  a  successful  treatment  will  gradually  show 
a  lowering  of  the  metabolic  rate;  if  from  hypo- 
thyroidism,  successful  treatment  will  reveal  an  in- 
crease in  the  metabolic  rate. 

There  is  one  drawback  to  the  method :  It  is  not 
easy  to  carry  out,  and  requires  skillful  scientists  to 
handle  the  instrument. 

It  may  be  mentioned  in  passing  that  metabolic 
studies  have  been  undertaken  in  other  ductless 
glandular  diseases,  notably  the  pituitary,  but  so 
far  with  little  result ;  the  plus  and  minus  variations 
are  not  of  a  sufficiently  pronounced  character. 

In  any  case  we  may  conclude  with  Dr.  Boothby, 
of  the  Kochester  Clinic,  that  "the  basal  metabolic 
rate,  which  is  a  determination  of  the  heat  produc- 
tion in  a  person  under  standard  conditions,  serves 


42        GLANDS  IN  HEALTH  ANP  DISEASE 

as  a  measurement  of  the  most  fundamental  process 
of  life  itself.  Variations  of  the  heat  production, 
and  alterations  in  the  body  temperature  are  to  be 
considered  rightly  a  means  of  fundamental  disease 
classification,  and  the  basal  metabolic  rate  serves 
as  an  accurate  diagnostic  aid  in  the  recognition  of 
the  presence  or  absence  of  hyper-  (and  hypo-)  thy- 
roidism." 

All  this  is  very  true  provided  the  diagnosis  does 
not  merely  confine  itself  to  a  determination  of 
the  basal  metabolism  of  the  patient;  for  increases 
in  basal  metabolism  are  obtained  in  pernicious 
anemia  or  leukemia  (increase  in  the  number  of 
leucocytes  in  the  blood)  or  fever.  These,  however, 
can  be  readily  differentiated  from  goiter  afflictions. 


CHAPTER  in 

THE  PARATHYROIDS 

Attached  to  the  thyroid  are  four  small  organs, 
weighing  in  all  not  more  than  two  grains,  which 
are  known  as  the  "parathyroids"  ("para"  means 
"near").  For  a  long  time  these  organs  were 
not  distinguished  from  the  thyroid  proper,  and 
even  when  discovered  and  described,  they  were — 
and  by  some  still  are — regarded  as  part  of  the 
larger  gland.  The  concensus  of  opinion,  however, 
seems  to  be  in  favor  of  the  belief  that  the  para- 
thyroids are  independent  organs  with  an  indepen- 
dent action  all  their  own;  and  that  if  they  are  re- 
lated to  the  thyroid,  the  relationship  is  no  closer 
than  that  of  any  other  two  ductless  glands  in  the 
body.  For  much  of  our  knowledge  of  the  para- 
thyroids we  are  indebted  to  the  French  physiolo- 
gist, Gley. 

Tetcmy. — The  removal  of  the  parathyroids  in  an 
animal,  or  their  decay  or  removal  in  man,  gives 
rise  to  the  condition  known  as  "tetany"  (which, 
by  the  way,  must  not  be  confused  with  tetanus  or 
lockjaw).  This  "tetany"  is  characterized  by  the 

43 


44         GLANDS  IN  HEALTH  AND  DISEASE 

sudden  involuntary  contractions  of  the  muscles 
and  extremities.  "The  fits  are  sometimes  frequent, 
but  more  often  occur  at  long  intervals."  The  res- 
piratory tract,  the  heart,  and  the  body  temperature 
are  also  affected.  The  illness  is  very  often  pro- 
longed, and  often  terminates  fatally.  There  is  a 
loss  in  weight,  indicating  a  disturbed  metabolism. 
The  presumption  that  the  metabolism  of  bone,  and 
particularly  that  relating  to  calcium,  is  affected, 
has  experimental  support,  in  that  the  administra- 
tion of  calcium  sometimes  relieves  the  sufferer. 

That  tetany  is  the  result  of  the  absence  of  the 
parathyroids  is  clear  enough  when  we  consider 
that  the  administration  of  parathyroid  extract 
relieves  the  patient,  at  least  temporarily.  You  see, 
we  are  here  dealing  with  a  case  of  hypo-parathy- 
roidism,  just  as  in  cretinism  and  in  myxedema  we 
dealt  with  instances  of  hypo-thyroidism ;  and  just 
as  the  thyroid  secretes  a  specific  hormone  the  ab- 
sence of  which  gives  rise  to  cretinism  in  the  child 
and  myxedema  in  the  adult,  so  the  parathyroid 
secretes  a  hormone  the  absence  of  which  gives  rise 
to  tetany.  Notice  that  the  most  important  piece 
of  evidence  for  this  view  is  that  in  both  cases  the 
symptoms  disappear  upon  the  administration  of 
the  extract  of  the  appropriate  gland.1 

*The  results  with  parathyroid  extracts  are  more  conflicting 
than  those  with  thyroid  ones.  A  safer  position  to  take  would  be 
to  say  that  the  symptoms  of  tetany  can  be  removed  by  "grafting" 
the  gland,  rather  than  by  administering  an  extract  of  the  gland. 


THE  PARATHYROIDS  45 

Koch  has  found  that  in  tetany  there  is  an  ex- 
cessive elimination  of  guanidine,  an  important 
nitrogenous  substance  that  plays  a  part  in  the 
metabolism  of  the  body ;  and  he  has  postulated  the 
theory  that  tetany  is  due  to  an  intoxication  of  the 
central  nervous  system  by  this  guanidine, — a  view 
that  has  a  number  of  opponents. 

It  may  now  be  asked,  if  hyper-secretion  of  the 
thyroid  may  give  rise  to  exophthalmic  goiter,  what 
does  hyper-secretion  of  the  parathyroid  give  rise 
to?  We  are  not  very  sure.  We  have  reached  the 
end  of  the  land  of  fact  and  have  now  begun  our 
journey  in  that  of  speculation.  Since  one  of  the 
chief  objects  in  writing  this  book  is  to  distinguish 
fact  from  fancy,  and  therefore  to  combat  much  that 
has  been  written  on  the  subject  of  the  ductless 
glands,  we  shall  avoid  entering  this  land  of  specu- 
lation. 

The  study  of  the  parathyroids  makes  clear  why 
in  operations  involving  the  removal  of  thyroid  tu- 
mors, the  earlier  surgeons  were  much  troubled, 
because  very  often  an  apparently  successful  opera- 
tion would  be  marred  by  the  development  of  tetany 
in  the  patient.  We  now  can  attribute  such  a  re- 
sult to  the  removal  of  the  parathyroids  as  well  as 
to  that  of  the  thyroid.  The  surgeon  of  the  present 
day,  engaged  in  an  operation  of  this  kind,  invari- 
ably leaves  at  least  two  of  the  four  parathyroids, 
for  not  the  least  remarkable  of  the  many  remark- 


46        GLANDS  IN  HEALTH  AND  DISEASE 

able  facts  gathered  about  these  ductless  glands  is 
that  even  when  only  part  of  the  organ  remains  in 
the  body,  it  still  functions,  though,  of  course,  not  as 
well  as  the  entire  organ  would. 


CHAPTER  IV 

THE  PITUITARY  GLAND 

It  seems  hardly  credible  that  a  piece  of  tissue 
weighing  one-sixtieth  of  an  ounce,  "the  size  'of  a 
hazel-nut,"  and  lying  at  the  base  of  the  skull, 
should,  perhaps,  be  involved  in  the  production  of 
giants  on  the  one  hand,  and  dwarfs  on  the  other; 
that  it,  like  the  thyroid  gland,  should  profoundly 
influence  metabolic  and  brain  functions,  growth 
and  life  itself;  yet  such  seems  to  be  the  case  with 
the  pituitary  gland  (sometimes  called  "hypophysis 
cerebri").  The  conflicting  results  that  encumber 
much  of  the  work  on  this  gland — and  on  other 
ductless  glands  for  that  matter — are  due  to  the 
almost  insurmountable  difficulties  that  the  surgeon 
encounters  in  locating  and  removing  the  gland, 
without  at  the  same  time  bringing  about  secon- 
dary reactions  that  are  due  to  causes  other  than 
the  removal  of  the  pituitary.  Much  of  what  we 
know  we  owe  to  the  genius  of  Harvey  Gushing, 
professor  at  Harvard. 

The  pituitary  described. — The  pituitary  body, 
like  the  thyroid,  consists  of  two  parts,  two  "lobes," 

47 


48        GLANDS  IN  HEALTH  AND  DISEASE 

and  is  situated  in  a  depression  of  a  wedge-shaped 
bone  lying  at  the  base  of  the  skull.  It  was  an  organ 
not  unknown  even  to  such  ancients  as  Galen  and 
Vesalius,  who  thought  that  it  was  involved  in  the 
formation  of  nasal  secretions  (hence  the  name 
"pituitary"  from  the  Latin  "pituita,"  meaning 
"phlegm") .  Yet,  as  Professor  Gushing  has  pointed 
out,  Lower,  as  far  back  as  1672,  in  a  paper  entitled 
"Dissertatio  de  Origine  Catarrhi"  says,  "For 
whatever  serum  is  separated  in  the  ventricles  of 
the  brain  and  tissues,  out  of  them  through  the  in- 
fundibulum  to  the  glandula  pituitaria  distils  not 
upon  the  palate,  but  is  poured  again  into  the  blood 
and  is  mixed  with  it" — which  is  a  very  modern  way 
of  defining  a  ductless  gland. 

The  vagueness  attaching  to  the  function  of  the 
pituitary  remained  such  that  the  French  were  fond 
of  calling  it  "Porgane  enigmatique."  A  distinct 
advance  was  made  in  1886  when  Marie,  a  French 
scientist,  associated  a  peculiar  disease  character- 
ized by  the  enlargement  of  certain  bones  of  the 
body,  and  which  he  called  "acromegaly,"  with  a 
tumor  of  the  pituitary.  The  next  step  was  a  per- 
fectly natural  one;  the  tumor  had  to  be  removed. 
When  this  was  done  other  strange  symptoms  made 
themselves  manifest,  due  in  most  part,  as  we  know 
to-day,  to  glandular  insufficiency,  and  also,  to  some 
extent,  to  imperfect  operations.  Marie  formed  the 
opinion  that  "acromegaly"  was  a  disease  due  to  a 


THE  PITUITAEY  GLAND  49 

deficiency  of  pituitary  activity,  and  for  years  scien- 
tists blindly  believed  in  this  theory,  attempting  by 
extirpation  experiments  on  animals  to  reproduce 
acromegalic  symptoms.  All  such  experiments  re- 
sulted in  failure.  To-day  we  know  the  reason  why. 
The  acromegalic  in  all  probability  suffers  from  an 
excess  rather  than  from  a  deficiency  of  pituitary 
hormone,  or  hormones. 

Only  since  1895  has  intelligent  guesswork  given 
place  to  a  fair  amount  of  knowledge. 

Removal  of  the  pituitary. — Complete  removal  of 
the  pituitary  gland  causes  death.  Innumerable 
experiments  with  puppies  show  that  death  results 
in  from  two  to  thirty  days.  Where  the  life  of  the 
animal  is  prolonged,  a  post-mortem  examination 
reveals  that  a  portion  of  the  gland  still  remains. 
Gushing,  as  the  result  of  some  200  such  extirpa- 
tions on  dogs,  has  come  to  the  following  important 
conclusions:  that  a  prolongation  of  life,  if  not  a 
complete  recovery,  is  possible  by  transplanting  the 
gland  into  an  animal  that  had  had  its  pituitary 
removed;  that  whenever  the  animal  survives  the 
operation,  it  is  because  the  gland,  and  more  particu- 
larly the  anterior  1  portion  of  it,  has  not  been  com- 
pletely removed;  and  that  when  the  posterior  por- 
tion alone  is  removed,  the  animal  does  not  die.  It 
follows  then  that  the  pituitary  is  a  gland  essential 

1Any  part  nearer  the  head  than  another  part  is  anterior  to 
the  latter ;  if  farther  away  it  is  posterior. 


50        GLANDS  IN  HEALTH  AND  DISEASE 

to  life,  and  that  the  anterior  portion  is  more  essen- 
tial than  the  posterior. 

Partial  removal  of  the  gland,  giving  rise  to  hypo- 
pituitarism,  does  not  as  a  rule  end  fatally,  but 
brings  about  changes  in  the  animal  that  in  some 
respects  resemble  hypo-thyroidism ;  it  becomes  fat, 
it  looks  dull,  and  the  sexual  organs  are  very  im- 
perfectly developed.  The  animal  also  shows  a 
greater  tolerance  for  sugars  (see  the  chapter  on 
the  pancreas),  so  that  more  than  the  normal  quan- 
tity of  carbohydrate  can  be  taken  care  of ;  and  the 
animal  converts  it  into  fat  and  stores  it  as  such. 
But  more  characteristic  still  is  the  effect  on  growth. 
If  two  pups  of  the  same  age  and  from  the  same 
litter  are  taken,  and  one  has  part  of  its  pituitary 
removed,  at  the  end  of  twelve  months  the  experi- 
mental animal  will  look  less  than  one-half  the  size 
of  the  control  one.  This  remarkable  influence  that 
the  pituitary  has  on  the  growth  of  an  animal  can 
best  be  shown  with  young  pups.  In  the  mature 
animal  the  other  features  alone  become  dominant. 

In  man,  as  in  the  animal,  the  growth  factor  is 
more  involved  if  hypo-pituitarism  shows  itself  be- 
fore adolescence.  The  individual  remains  small 
and  fat;  his  sex  organs  show  little  development; 
and  such  secondary  sexual  features  as  the  forma- 
tion of  hair  on  the  face  fails  to  appear.  The  tem- 
perature is  subnormal,  the  pulse  slow.  He  exhibits 
a  drowsiness  and  torpidity  "like  an  animal  about 


THE  PITJJHTARY  GLAND  51 

to  undergo  hibernation."  Sometimes  there  are 
psychic  derangements;  and  even  epilepsy  is  not  un- 
common. Dr.  Tucker,  in  summarizing  200  cases 
of  epilepsy,  declares  that  63  of  this  number  showed 
some  pituitary  disturbance,  28  with  an  inclination 
toward  the  hypo-  condition.  He  further  states  that* 
feeding  these  patients  with  extracts  of  pituitary 
gland  had  a  beneficial  effect,  "not  infrequently 
leading  to  a  cure." 

The  dwarf  and  hypo-pituitarism. — Of  uncommon 
interest  is  the  inference  that  the  dwarf  is  really 
one  who  suffers  from  hypo-pituitarism.  While  we 
need  much  more  proof  to  clinch  the  matter,  some 
evidence  is  not  wanting  in  this  direction.  The  few 
studies  that  have  been  made  show  such  pituitaries 
to  be  small  and  atrophied.  However,  as  Professor 
Cushing  says :  "It  is  not  unlikely  that  under  the 
term  ateliosi  and  prageria,  introduced  by  Gilford 
to  designate  continuous  youth  and  'premature  old 
age',  examples  of  pituitary  disease  may  have  been 
incorporated.  Yet  Herter  describes  a  type  of  in- 
fantilism which  is  clearly  attributable  to  chronic 
intestinal  infection ;  and  Osborne  and  Mendel  have 
shown  that  feeding  young  rats  with  isolated  pro- 
teins markedly  inhibits  their  growth,  though  nor- 
mal weight  is  maintained.1  There  are  still  other 
factors.  Hence  it  is  unwise  to  lay  too  great  stress 

*See  the   author's   chapter   on  Amino- Acids   in   his  book  on 
Vitamines. 


52        GLANDS  IN  HEALTH  AND  DISEASE 

on  anything  other  than  the  possibility  of  an  indirect 
pituitary  participation  in  the  dwarfed  stature 
characterizing  the  many  types  of  infantilism." 

Different  parts  of  the  pituitary  have  different 
properties. — It  has  recently  been  shown  that  in 
reality  the  two  parts  of  the  pituitary  have  two 
very  different  functions — the  anterior  part  being 
the  one  that  affects  stature,  and  the  posterior  por- 
tion the  one  that  influences  fat  formation  and  the 
development  of  the  sexual  organs.  That  the  an- 
terior fragment  of  the  pituitary  is  the  growth- 
promoting  factor  may  be  inferred  from  an  experi- 
ment already  cited:  if  the  entire  pituitary  is  re- 
moved, death  results ;  if  part  of  it  is  removed,  and 
a  portion  of  the  anterior  lobe  remains  behind,  death 
does  not  result,  but  we  get  a  dwarfed  condition. 
To  prove  that  this  dwarfed  condition  of  the  animal 
is  the .  result  of  an  insufficient  anterior  lobe — of 
insufficient  hormone  produced  by  that  lobe — and 
not  due  to  the  removal  of  the  posterior  portion,  the 
latter  alone  may  be  removed,  when  it  will  be  seen 
that  there  is  no  alteration  in  stature. 

The  growth-promoting  factor  in  the  pitwtary.— 
Professor  Kobertson,  formerly  at  the  University  of 
California,  and  now  at  the  University  of  Adelaide, 
Australia,  has  published  an  extensive  series  of 
studies  within  the  past  few  years  on  the  growth- 
promoting  factor  in  the  anterior  lobe  of  the  pitui- 
tary. He  has  isolated  a  substance  from  it  which  he 


THE  PITUITARY  GLAND  53 

calls  "tethelin"  (from  the  Greek  "tethelos,"  grow- 
ing) ,  and  which  he  considers  the  growth -promoting 
factor.  Its  analysis  shows  it  to  be  related  to  the 
phosphatids,  a  group  of  important  physiological 
compounds  present  in  all  cells.  These  results  need 
confirmation.1 

The  function  of  the  posterior  lobe  of  the  pitui- 
tary.— If  surgical  methods  and  clinical  observation 
point  to  the  anterior  lobe  as  the  growth-promoting 
portion  of  the  pituitary,  what,  it  may  be  asked,  is 
the  function  of  the  posterior  body?  We  have  al- 
ready seen  that  surgical  removal  of  the  posterior 
body  is  not  followed  by  any  extreme  changes  in  the 
animal;  on  the  other  hand,  an  extract  of  the  pos- 
terior lobe,  when  injected  into  the  blood,  produces 
an  increase  in  blood  pressure,  much  like  adrenaline 
from  the  adrenal  glands  (which  see).  Though 
Oliver  and  Schafer  were  the  first  (in  1895)  to  show 
the  effects  on  blood  pressure  of  an  injection  of  an 
extract  obtained  from  the  whole  gland,  it  was  left 

1For  the  benefit  of  the  student  of  science  the  principle  that 
Robertson  employs  in  isolating  his  tethelin  will  be  given;  un- 
doubtedly much  of  value  is  to  be  found  in  this  pioneer,  though 
somewhat  inconclusive  study:  The  anterior  lobe  is  ground  with 
anhydrous  sodium  and  calcium  sulphates,  dried  over  the  water 
bath,  pulverized  and  extracted  with  boiling  alcohol,  filtered,  and 
the  filtrate  evaporated  somewhat  under  reduced  pressure,  mixed 
with  one  and  one-half  times  its  volume  of  ether,  the  precipitate 
redissolved  in  alcohol  and  reprecipitated  with  ether.  The  final 
product  is  dried  over  sulphuric  acid  at  30  to  35  degrees  (cent.). 
"From  the  constancy  of  its  phosphorus  and  its  nitrogen  content 
the  substance  would  appear  to  be  a  chemical  unit."  Professor 
Robertson  has  not  yet  ascertained  its  exact  chemical  configuration. 


54:        GLANDS  IN  HEALTH  AND  DISEASE 

to  Howell,  the  physiologist  at  Johns  Hopkins,  to 
prove  three  years  later  that  the  effect  was  due  to 
the  posterior  lobe  alone. 

While  there  are  resemblances  between  the  action 
of  adrenaline  and  that  of  the  hormone  in  the  pos- 
terior lobe  of  the  pituitary,  there  are  also  some 
striking  differences.  For  example,  the  action  of 
the  pituitary  hormone  is  apt  to  be  of  a  more  pro- 
longed nature.  Again,  a  second  injection  of 
adrenaline  repeats  the  action  of  a  first  injection; 
a  second  injection  of  the  pituitary  hormone  may 
reverse  the  action  of  a  first  injection.  There  may 
actually  be  a  decrease,  instead  of  an  increase  in 
blood  pressure.  Or  again,  on  the  arteries  of  the 
kidney  the  two  behave  diametrically  opposite: 
adrenaline  constricts  them  and  pituitary  hormone 
(which  we  shall  refer  to  as  "pituitrin,"  and  to 
which  we  shall  refer  subsequently)  dilates  them. 
Pituitrin,  indeed,  causes  quite  a  remarkable  in- 
crease in  urinary  flow,  and  has  established  itself 
as  a  useful  diuretic  (a  substance  that  increases  the 
secretion  of  urine). 

Properties  of  pituitrin. — The  action  of  pituitrin 
on  the  flow  of  milk  from  the  mammary  gland  is 
no  less  striking  than  its  property  as  a  diuretic,  to 
which  reference  has  just  been  made.  It  does  not 
seem,  from  the  experiments  conducted,  that  the 
pituitrin  actually  increases  the  quantity  of  milk 
secreted;  rather,  it  accelerates  the  discharge  once 


THE  PITUITAKY  GLAJSTD  55 

the  milk  has  accumulated.  "The  pituitrin,"  says 
Macleod,  "stimulates  the  muscular  fibers  of  the 
ducts  of  the  mammary  glands,  thus  squeezing  out 
the  milk  contained  in  them." 

One  other  property  of  this  pituitrin  must  be  re- 
ferred to.  We  have  noticed  that  partial  removal 
of  the  pituitary  in  animals,  giving  rise  to  hypo- 
pituitarism,  is  followed  by  an  increased  capacity 
for  carbohydrate  storage  (in  the  shape  of  fat). 
We  find,  on  the  contrary,  that  injection  of  pituitrin 
decreases  sugar  tolerance  to  such  an  extent  as  to 
give  rise  to  sugar  in  the  urine.  Evidently  it  is 
the  lack  of  a  sufficient  quantity  of  this  hormone  in 
the  animal  suffering  from  hypo-pituitarism  that 
gives  rise  to  an  increased  sugar  tolerance.  All  of 
which  is  in  favor  of  the  view  that  pituitrin,  like 
adrenaline,  like  the  pancreatic  hormone  ( see  under 
pancreas),  plays  a  part  in  carbohydrate  metabo- 
lism, though  it  by  no  means  follows  that  the  three 
parallel  one  another  in  their  action. 

Pituitrin  not  a  chemically  pure  product. — We 
have  given  the  name  "pituitrin"  to  the  hormone  (or 
hormones)  present  in  the  posterior  lobe  of  the 
pituitary.  It  should  now  be  made  quite  clear  that 
this  hormone  has  not  been  isolated  in  the  pure  state 
at  all ;  that  "pituitrin,"  of  which  there  are  several 
varieties  on  the  market,  is  merely  a  concentrated 
extract  of  the  posterior  portion  of  the  lobe,  usually 
obtained  by  first  getting  rid  of  the  protein  present 


56         GLANDS  IN  HEALTH  AND  DISEASE 

in  the  gland,  and  then  sterilizing  the  remainder. 
The  fact  that  sterilization  does  not  destroy  the 
activity  of  the  hormone  is  further  evidence  that 
hormones  and  vitamines  (and  enzymes)  are  prob- 
ably not  very  closely  related  (see  also  under  secre- 
tin).  The  suggestion  that  the  active  principle  of 
the  posterior  lobe  is  none  other  than  histidine,  an 
amino-acid  familiar  enough  to  the  organic  and 
physiological  chemists1  (suggested  by  Professor 
Abel,  of  Johns  Hopkins,  in  1919)  has  not  been 
confirmed. 

Difficulty  in  interpreting  data. — While  in  a  sense 
our  knowledge  of  the  properties  of  the  posterior 
and  anterior  lobes  of  the  pituitary  is  increasing,  our 
difficulty  in  interpreting  data  is  not  diminishing. 
If  the  anterior  lobe  is  affected  and  not  the  posterior 
one,  we  get  diminished  size  and  little  else.  If  both 
are  affected,  we  get  a  combination  of  symptoms. 

And  still  another  complication  arises.  As  we 
shall  see  in  a  minute,  it  does  not  always  follow 
that  when  the  pituitary  is  affected  we  get  hypo- 
pituitarism.  It  may  result  in  hyper-pituitarism — 
in  an  excessive  formation  of  pituitary  hormone  or 
hormones.  Now  it  is  quite  conceivable  that  when 
one  lobe  shows  such  a  tendency,  another  may  show 
the  opposite  tendency;  and  yet,  since  the  function 
of  each  lobe  is  different,  this  does  not  mean  that  a 

aSee  the  chapter  on  Amino- Acids  in  the  author's  book  on 
Vitamines. 


THE  PITUITARY  GLAND  57 

neutral  or  normal  condition  will  result  just  because 
the  two  lobes  pull  in  opposite  directions.  If  we 
bear  these  factors  in  mind — and  they  probably 
apply  to  the  thyroid  and  to  other  ductless  glands — 
we  shall  appreciate  the  tasks  of  the  physiologist 
and  the  physician. 

Professor  Cushing's  opinion  of  the  problem. — 
Professor  Gushing  in  a  recent  (June,  1921)  article 
on  the  disorders  of  the  pituitary  gland,  has  this 
to  say :  "In  the  case  of  pituitary  disorders  we  are 
not  far  beyond  the  stage  of  the  tumor.  One  may 
recognize  outspoken  acromegaly  without  a  roent- 
genogram  of  the  sella  (the  place  where  the  pitui- 
tary is  situated),  just  as  one  may  recognize  ex- 
ophthalmic goiter  without  seeing  the  neck.  But  in 
the  absence  of  neighboring  pressure  signs,  to  say 
that  a  child  who  is  undersized,  or  fat,  or  whose 
dentition  or  adolescence  is  delayed,  or  that  an  adult 
who  has  the  texture  and  color  of  skin,  the  adiposity, 
impotence,  subnormal  temperature,  and  so  on, 
known  to  characterize  certain  individuals  with  hy- 
pophyseal  adenomas  (pituitary  tumors),  is  really  a 
subject  of  pituitary  want,  is  purely  a  matter  of 
guesswork.  If  this  admission  must  be  made  regard- 
ing these  fairly  characteristic  symptoms,  what  is 
there  to  say  of  a  pluriglandular  (affecting  several 
glands)  complex  except  to  acknowledge  an  abysmal 
ignorance?  .  .  .  Only  of  late  with  the  development 
of  roentgenology  and  the  more  extended  use  of  the 


58         GLANDS  IN  HEALTH  AND  DISEASE 

ophthalmoscope  (a  mirror  used  in  examining  the 
interior  of  the  eye)  and  perimeter  (an  instrument 
that  measures  the  field  of  vision)  can  a  diagnosis  of 
pituitary  disease  apart  from  acromegaly  be  made 
with  any  probability.  Unlike  the  thyroid  enlarge- 
ment, a  hypophyseal  growth  can  be  determined 
only  by  indirect  methods;  for  next  to  the  brain 
itself,  the  hypophysis  lies  in  possibly  the  best  pro- 
tected and  most  inaccessible  place  in  the  body — 
one  reason  for  assuming  that  it  may  be  a  most  im- 
portant member  of  the  endocrine  series." 

Use  of  pituitary  extract. — Now  it  is  time  to 
answer  the  question  that  must  arise  in  the  minds 
of  readers:  If  a  person  suffering  from  hypo- 
thyroidism,  and  showing  symptoms  of  myxedema, 
can  be  cured  by  being  fed  with  thyroid  extract,  is 
it  possible  to  cure  sufferers  from  hypo-pituitarism 
by  feeding  them  with  pituitary  extract?  It  is  in 
many  cases,  though  one  can  point  to  just  as  many 
cases  where  such  treatment  has  been  of  no  avail. 
Pituitrin  extract  has  been  given  by  mouth  and  by 
means  of  an  injection;  and  a  few  transplantation 
experiments  have  been  performed  on  animals;  but 
the  results  have  been  only  moderately  successful; 
certainly  not  nearly  as  successful  as  when  thy- 
roid extract  is  administered  in  the  corresponding 
thyroid  disease.  Why  this  should  be  is  not  clear, 
unless  we  admit  that  a  hypophyseal  insufficiency 
creates  at  times  such  a  disordered  organism,  that 


THE  PITUITARY  GLAND  59 

treatment  by  means  of  an  extract  obtained  from 
any  one  gland,  or  even  from  a  number  of  glands, 
is  no  longer  sufficient. 

Quackery  in  medicine. — Perhaps  in  no  depart- 
ment of  medicine  has  quackery  flourished  so  much 
as  in  that  dealing  with  the  ductless  glands,  and 
more  particularly  with  the  pituitary.  The  over- 
enthusiastic  scientist  has  joined  hands  with  the 
pseudo-scientist,  and  both  have  provided  ample  ma- 
terial to  the  charlatan  to  advertise  his  goods,  and  to 
ingratiate  himself  with  an  all-too-credulous  public. 

I  cannot  resist  quoting  Professor  Cushing's  very 
pertinent  remarks :  "Children  are  either  too  short 
or  too  tall,  too  fat  or  too  lean.  Their  adolescence 
is  too  early  or  too  late ;  they  have  too  little  or  too 
much  hair.  They  are  intellectually  backward  or 
stupid,  even  defective  or  epileptic  ...  all  this 
needs  attention  and  can  be  corrected  by  some  whole- 
gland  extract,  usually  with  a  pinch  of  thyroid 
thrown  in. 

"Pituitary  extract  is  advocated  in  parturition, 
shock,  baldness,  impotence,  epilepsy,  and  a  multi- 
tude of  other  conditions  which  have  hitherto 
baffled  us ;  and  if  it  does  not  suffice  by  itself  you  are 
earnestly  recommended,  according  to  the  directions 
'in  the  enclosed  folder,  to  try  this  or  that  combina- 
tion of  hormones  which  contains  the  active  prin- 
ciple of  several  glands  .  .  . 

"I  know  of  nothing  comparable  to  the  present 


60        GLANDS  IN  HEALTH  AND  DISEASE 

furore  regarding  the  administration  of  glandular 
extract  unless  it  be  the  plant  pharmacology  of  the 
middle  ages.  ...  A  patient  is  bilious — therefore 
he  has  some  disease  of  the  liver.  The  leaves  of  a 
certain  plant  resemble  in  their  color  and  appear- 
ance the  surface  of  the  liver — therefore  a  concoc- 
tion of  these  leaves  is  good  for  biliousness,  and  the 
plant  comes  to  be  called  hepatica.  But  then,  lest 
it  may  not  really  do  this,  we  will  add  several  other 
things  to  the  concoction  as  well.  This  is  about  the 
basis  on  which  the  glandular  extracts  are  admin- 
istered to-day.  And  it  will  be  noted  that  most  of 
them  contain  a  certain  amount  of  thyroid  extract, 
which  possibly  is  the  only  one  of  these  sub- 
stances having  any  definite  action  when  given  by 
mouth.  ,  .  . 

"Surely  nothing  will  discredit  the  subject  so 
effectively  as  pseudo-scientific  reports  which  find 
their  way  from  the  medical  press  into  advertising 
leaflets,  where,  cleverly  intermixed  with  abstracts 
from  researches  of  actual  value,  the  administration 
of  pluriglandular  compounds  is  promiscuously  ad- 
vocated for  a  multitude  of  symptoms,  real  and  fic- 
titious. The  Lewis  Carroll  of  to-day  would  have 
Alice  nibble  from  a  pituitary  mushroom  in  her  left 
hand  and  a  lutein  (a  pigment  obtained  from  a  por- 
tion of  the  ovary)  one  in  her  right  hand  and  presto! 
she  is  any  height  desired !" 

Pituitary  extract  and  the  development  of  chick- 


THE  PITUITARY  GLAND  61 

ens.— One  rather  remarkable  experiment  with 
chickens,  performed  by  Dr.  L.  N.  Clark,  must  be 
cited:  "In  the  first  experiment,  35  white  Leghorn 
hens,  as  well  as  two  cockerels  of  the  same  breed 
with  which  they  were  mated,  each  received  daily 
during  eight  days  the  equivalent  of  20  milligrams 
(0.0006  ounces)  of  fresh  pituitary  substance  in 
addition  to  their  usual  food.  By  the  fifth  day  the 
egg  production  of  the  batch  was  raised  from  an 
average  of  18  per  diem  to  33 ;  the  beneficial  effect, 
although  diminishing,  was  maintained  for  several 
days  after  the  pituitary  had  been  taken  off.  And 
not  only  was  the  output  of 'eggs  largely  fincreased 
as  compared  with  the  controls,  but  the  fertility  of 
the  eggs  and  the  hatching  out  of  the  chicks  was 
extraordinarily  enhanced.  In  order  to  test  the 
matter  further,  a  second  experiment  was  performed 
with  as  many  as  655  one-year-old  white  Leghorn 
hens  (kept  without  males),  the  same  dose  as  be- 
fore being  given  to  each  hen  during  four  days.  The 
average  daily  number  of  eggs  laid  by  the  batch 
during  the  four  days  preceding  the  pituitary  feed- 
ing was  233;  during  the  four  days  succeeding  the 
administration,  352.  These  experiments  were  made 
at  a  time  of  the  year  when  the  egg  production  of 
the  hens  was  tending  to  diminish  rather  than  to 
increase."  ( Quoted  by  Professor  -  Schafer. ) 

Hyper-pituit&rism* — Marie,  a  French  physician, 
active  some  forty  years  ago,  was  the  first  to  give 


62        GLANDS  IN  HEALTH  AND  DISEASE 

the  name  "aeromegaly"  (enlargement  of  the  ex- 
tremities) to  that  disease  which  produces  an  en- 
largement of  bones,  soft  part  of  hands  and  feet,  and 
face,  and  in  which  the  individual  assumes  giant- 
like proportions.  He  rightly  diagnosed  such  cases 
as  being  due  to  some  pituitary  disorder,  but  for 
some  time  he  was  of  the  opinion  that  aeromegaly 
was  due  to  lack  of  secretion  in  the  gland.  When, 
however,  experiments  on  animals  showed  that  the 
partial  removal  of  the  gland  gave  rise  not  to  giants 
but  to  dwarfs,  the  view  was  adopted  that  aerome- 
galy was  a  disease  resulting  from  a  hyper-,  rather 
than  a  hypo-secretion;  that  is  to  say,  then,  to  an 
excessive  secretion  of  pituitary  hormone.  It  is  un- 
fortunate in  the  extreme  that  so  far  all  attempts  to 
simulate  aeromegaly  by  feeding  animals  with  large 
quantities  of  pituitary  extract  have  failed ;  so  that 
our  evidence  at  best  is  somewhat  unsatisfactory. 
The  reader  will  remember  that  in  this  respect  thy- 
roid therapy  stands  on  firmer  footing;  for  hyper- 
thyroidism  can  be  fairly  closely  imitated  in  the  ani- 
mal by  feeding  it  with  sufficient  quantities  of  thy- 
roid extract. 

Symptoms  in  aeromegaly. — The  symptoms  in 
aeromegaly  do  not  make  their  appearance  sud- 
denly; the  changes  in  the  individual  are  quite 
gradual,  as  with  many  of  the  diseases  involving 
the  ductless  glands.  At  first  the  person  may  notice 
nothing  more  than  eye  strain  and  dimmed  vision. 


THE  PITUITARY  GLAND  63 

This  may  be  due  to  a  tumor  in  the  gland  pressing 
on  the  optic  nerve.  But  then  comes  the  gradual 
enlargement  of  the  head  and  extremities  that  can 
leave  no  further  room  for  doubt.  The  face  becomes 
big  and  coarse-looking,  the  head  rather  flattened. 
An  X-ray  examination  of  the  fingers  shows  the 
bones  to  be  enlarged.  The  entire  skeleton  in- 
creases in  size,  sometimes  to  huge  proportions. 
Then  also  we  have  an  overgrowth  of  hair,  under- 
developed sexual  glands,  and  a  probable  onset  of 
diabetes, — which  may,  however,  be  of  a  temporary 
nature. 

Cure  in  acromegaly. — We  have  no  easy  cure  for 
this  disease.  Surgical  interference  may  seem  an 
obvious  remedy.  This  is  a  dangerous  procedure, 
however,  and  is  undertaken  only  in  extreme  cases. 
Fortunately,  true  cases  of  acromegaly  are  rare,  and 
experience  has  shown  that  nature  and  time  often 
act  as  effective  curative  agents. 

As  a  rule  the  case  presented  to  the  physician  and 
surgeon  is  by  no  means  a  clear-cut  one.  It  may 
be  one  where  hyper-pituitarism  predominates,  giv- 
ing us  an  example  of  gigantism  if  the  patient  is 
affected  early  in  life,  or  acromegaly — not  so  pro- 
nounced as  gigantism — if  later  in  life;  or  it  may 
belong  to  the  hypo-pituitary  class,  with  reverse 
symptoms,  such  as  under-size,  adiposity  and  sexual 
infantilism,  if  early  in  life;  or  the  latter  two,  if 
later.  But  a  far  more  common  case,  and  one  that 


64:        GLANDS  IN  HEALTH  AND  DISEASE 

complicates  the  situation,  is  the  mixed  or  transition 
type,  exhibiting  some  features  of  the  hyper-  and 
the  hypo-  conditions  (cfo/s-pituitarism). 

Of  255  cases  that  have  come  under  Professor 
Cushing's  care,  200  showed  evidence  of  a  tumor — 
which  of  itself  may  give  rise  to  a  hyper-  or  hypo- 
condition,  or  to  a  mixture  of  both.  Of  these  200, 
180  were  operated  on,  and  among  the  latter  there 
were  few  acromegalics.  The  majority  exhibited 
various  forms  of  dyspituitarism. 

Professor  Gushing  writes:  "In  view  of  the  fact 
that  hyper-pituitarism,  so  far  as  glandular  secre- 
tion is  concerned,  is  a  condition  which  tends  to 
right  itself,  it  must  remain  for  the  time  being  a 
matter  of  uncertainty  as  to  whether  or  not  in  the 
absence  of  a  degree  of  hyperplasia  (excessive  multi- 
plication of  tissue  elements)  sufficient  to  cause 
neighborhood  symptoms,  operative  measures  can 
hold  out  any  promise  of  permanently  controlling 
the  disorder.  When,  however,  neighborhood  symp- 
toms have  arisen  owing  to  the  extreme  enlargement 
of  the  gland,  due  to  the' formation  of  an  adinoma- 
tous  struma  (a  tumor  in  an  enlarged  gland), 
whether  or  not  there  have  been  antecedent  symp- 
toms of  acromegaly,  the  surgical  aspects  of  the 
matter  stand  on  firmer  ground." 

Do  giants  suffer  from  hyper-pituitarism? — One 
is  attracted  by  the  hypothesis  that  giants  are  ex- 
amples of  men  suffering  from  hyper-pituitarism. 


THE  PITUITARY  GLAND  65 

Arthur  Keith,  the  sponsor  of  attractive  theories  on 
behalf  of  the  endocrine  glands,  writes,  "In  giants 
this  gland  [the  pituitary]  is  always  greatly  and 
abnormally  overgrown.  We  have  reasons  for  sup- 
posing that  it  has  thrown  a  drug  or  drugs  into  the 
blood  which  set  all  the  bone-builders  into  a  state 
of  frenzied  activity,  producing  the  dire  disease  of 
growth  called  gigantism."  These  claims  cannot  be 
maintained  without  many  qualifications. 

A  case  of  acromegaly. — Of  a  number  of  instruc- 
tive cases  described  by  Gushing  in  his  book  on  the 
pituitary — a  book  that  has  become  a  classic  in 
medical  literature — I  shall  cite  one  as  illustrating 
the  acromegalic  who  in  time  actually  suffers  from 
hypo-pituitarism — in  other  words,  a  complex  type. 

The  case  was  that  of  a  farmer,  age  35,  of  Dutch 
extraction  and  of  excellent  family  history.  A  hypo- 
physeal  tumor  caused  pronounced  neighborhood 
symptoms  with  almost  total  blindness.  There  had 
been  a  former  glandular  activity,  shown  by  a  ten- 
dency to  excessive  overgrowth,  traceable  to  the  ado- 
lescent period ;  and  by  subsequent  addition  of  acro- 
megalic changes  of  unusual  degree.  When  admit- 
ted to  the  hospital  the  patient,  on  the  contrary,  in- 
dicated a  condition  of  glandular  insufficiency,  as 
shown  by  adiposity  and  high  sugar  tolerance. 

As  to  his  history,  nothing  unusual  was  noticed 
in  the  farmer  until  he  was  13  years  old,  when  he 
began  to  grow  with  extreme  rapidity,  and  at  19 


66        GLANDS  IN  HEALTH  AND  DISEASE 

measured  about  six  feet  four  inches,  having  de- 
veloped into  a  powerful  man  of  unusual  strength, 
weighing  222  pounds.  He  was  intelligent  and  a 
good  student.  So  far  all  had  gone  well.  The  man 
was  an  excellent  type  of  a  physically  well-developed 
youth. 

At  23  he  had  a  severe  illness;  he  was  said  to  be 
"threatened  with  consumption."  At  25  there  seem 
to  have  been  no  traces  of  acromegaly.  He  and  his 
father  were  positive  that  a  second  growth  began 
when  he  was  27. 

About  1903 — at  28 — he  began  to  have  violent 
headaches  (due  to  a  tumor  of  the  pituitary,  and  to 
the  consequent  pressure  on  adjacent  parts) ;  also 
pains  in  the  extremities.  These  attacks  would  be 
followed  by  the  discharge  from  the  nose  of  quan- 
tities of  "slimy  mucus/'  occasionally  tinged  with 
blood,  and  relief  would  ensue  for  some  days  or 
weeks.  He  was  told  at  the  time  that  he  had  acro- 
megaly. Two  years  later  difficulty  in  sighting  his 
rifle  first  called  attention  to  a  failure  of  vision. 

In  1907  his  parents  realized  that  his  "features 
were  changing/5  and  that  he  was  "getting  large  all 
over,"  and  was  losing  his  strength  (this  was  dur- 
ing his  "second  period  of  growth" ) . 

When  admitted  into  Dr.  Cushing's  clinic — in 
1910 — he  had  become  very  weak  and  drowsy,  and 
tired  easily.  There  had  been  a  complete  loss  of 
libido  et  potentio  sexu&lis.  Beading  vision  was  lost 


THE  PITUITAKY  GLAND  67 

the  year  before.  The  left  eye  was  blind  and  the 
right  nearly  so.  His  appetite  was  large  and  he 
always  had  a  box  of  sweets  at  hand.  He  had  be- 
come very  constipated. 

The  patient's  height  was  six  feet  six  inches.  He 
weighed  269  pounds.  "Neither  these  measurements 
nor  the  photographs  give  more  than  a  scant  indica- 
tion of  his  extraordinary  size  and  the  disproportion 
of  such  parts  as  the  head,  hands  and  feet.  He  is 
a  veritable  Gargantua." 

The  X-ray  indicated  tumor  enlargement  of  the 
pituitary.  The  eyes  were  large,  protruding, 
widely  separated,  and  showed  a  divergent  squint 
(neighboring  symptom). 

The  hands,  always  large,  were  now  huge.  The 
feet  were  colossal :  formerly  he  could  wear  a  num- 
ber eleven  shoe,  but  now  he  had  to  have  them  spe- 
cially made. 

He  had  practically  no  beard,  and  except  for  a 
scant  pubic  growth  of  feminine  distribution,  the 
skin  of  the  trunk  and  extremities  was  practically 
hairless.  On  the  scalp  the  hair  was  abundant  and 
coarse. 

The  patient  was  operated  on  nine  days  after  ad- 
mission, and  the  glandular  tumor  thereby  removed. 
The  convalescence  was  uneventful. 

On  December  23,  six  days  after  the  operation, 
there  was  an  improvement  in  vision. 

Since  the  later  symptoms  were  those  of  hypo- 


68        GLANDS  IN  HEALTH  AND  DISEASE 

pituitarism  as  well,  glandular  feeding  was  insti- 
tuted. 

On  January  28  the  patient  felt  so  much  stronger 
and  less  nervous,  that  he  was  discharged. 

A  letter  received  from  the  patient  February  27 
reported  a  further  improvement  in  vision,  a  normal 
temperature,  and  no  constipation.  On  May  4  he 
reported  an  increase  in  weight  to  281  pounds  (just 
before  the  operation  this  weight  was  269).  On 
June  27  the  patient  was  seen  in  Los  Angeles.  The 
vision  in  the  right  eye  had  further  improved.  He 
recognized  colors.  He  was  less  nervous  and  less 
drowsy  than  before. 

A  bit  of  fancy? — At  the  International  Congress 
of  Eugenics,  held  in  New  York  in  September,  1921, 
a  session  was  given  over  to  the  influence  of  the 
endocrines  on  the  organism.  The  papers  presented 
were  of  the  type  that  belong  to  the  borderland  sepa- 
rating fact  from  fancy.  At  any  rate,  one  of  New 
York's  very  respectable  papers  had  headlines  such 
as  these :  "Says  glands  cause  gloom  and  crime. 
A  criminal  is  the  victim  of  chemical  reactions. 
Scientist  explains  why  a  white  man  is  white  and 
why  man  is  superior  to  woman."  One  of  the  papers 
dealt  with  the  development  of  man  from  the  mon- 
key, and  Professor  Polk,  Director  of  the  Depart- 
ment of  Anatomy  in  the  University  of  Amsterdam, 
discussed  the  first  change  in  man's  ape  ancestor, — 
the  suppression  of  his  hairy  covering.  He  argued 


THE  PITUITAKY  GLAND  69 

that  this  suppression  was  connected  with  pituitary 
activity !  It  would  seem  that  Darwin  in  developing 
his  theory  of  Natural  Selection,  quite  overlooked 
the  subject  of  endocrinology! 


CHAPTER  V 

THE  ADRENAL  GLANDS 

These  glands  consist  of  two  small  bodies  situated 
near  the  kidney  (hence  "adrenal"),  each  weighing 
about  one-seventh  of  an  ounce.  Sometimes  they 
are  called  "suprarenal  bodies,"  to  indicate  that 
they  are  found  above  the  kidney.  Sometimes  they 
are  referred  to  as  part  of  the  "chromaffin  system," 
to  indicate  that  their  cells  are  colored  brown  with 
chromic  acid. 

There  are  really  two  very  distinct  parts  to  the 
adrenal  gland :  the  "medullary  matter,"  a  marrow- 
like  body,  in  which  is  found  the  hormone  adrena- 
line (also  known  as  epinephrine  and  suprarenine), 
and  the  outer  organ,  the  "cortex,"  which  also  se- 
cretes a  vitally  necessary  substance  that  so  far, 
however,  has  baffled  isolation. 

History. — Eustachius,  the  great  anatomist  of  the 
sixteenth  century,  may  be  regarded  as  the  discov- 
erer of  the  adrenal  glands.  As  early  as  1789 
Cassan  made  the  observation  that  the  adrenals  of 
the  Negro  are  larger  than  those  of  the  European, 
from  which  he  drew  the  somewhat  far-fetched  con- 

70 


THE  ADRENAL  GLANDS  71 

elusion  that  the  gland  and  the  pigment  of  the  skin 
are  related.  In  a  modified  form,  this  view  of 
Cassan's  was  recently  brought  forward  at  the 
International  Congress  of  Eugenics.  Meckel,  an- 
other observer,  noticed  a  similar  enlargement  of 
the  gland  in  the  Negro,  but  he  decided  that  the  rela- 
tionship did  not  rest  with  the  pigment  of  the  skin, 
but  rather  with  the  genital  organs. 

Little  was  known  with  regard  to  the  function  of 
the  adrenals  until  1849,  when  Thomas  Addison, 
physician  at  Guy's  Hospital,  London,  made  the 
observation  that  a  disease  characterized  by  bronz- 
ing or  pigmentation  of  the  skin,  was  invariably 
accompanied  by  the  decay  of  the  adrenal  glands. 
This  observation  of  the  English  physician  led  to 
little  new  work,  however;  and  it  was  only  as  late 
as  1894  that  a  further  impetus  was  given  to  the 
entire  subject  by  Professor  Schafer's  discovery 
that  the  injection  into  the  body  of  an  adrenal  ex- 
tract increased  the  blood  pressure. 

Removal  of  the  gland.— Complete  removal  of  the 
gland  in  animals  is  followed  by  death  within  a  few 
days,  though  the  first  day  or  two  after  the  opera- 
tion may  fail  to  show  any  abnormality  or  disease. 
Partial  removal  is  not  as  a  rule  fatal,  though  vari- 
ous symptoms  may  make  their  appearance.  The 
administration  of  adrenal  extract  has  little  or  no 
effect.  Even  in  the  case  of  Addison's  disease,  which 
we  have  reason  to  believe  is  due  to  a  decreased  se- 


72        GLANDS  IN  HEALTH  AND  DISEASE 

cretion  of  the  gland,  feeding  with  an  extract  of  the 
gland  is  followed  by  no  beneficial  results — at  least 
none  that  last. 

Brown-Sequard,  whose  name  we  shall  encounter 
when  we  come  to  discuss  the  function  of  the  sex 
glands,  did  pioneer  work  on  the  adrenals  as  far 
back  as  1856.  He  removed  adrenal  glands  from 
44  rabbits,  nine  guinea-pigs,  two  rats  and  several 
dogs  and  cats.  Not  one  of  these  animals  survived 
the  operation  beyond  the  thirty-seventh  hour.  The 
critics,  ever  after  poor  Brown- Sequard,  severely 
criticized  his  work;  they  claimed  that  death  in  all 
cases  was  due  to  the  nature  of  the  operation,  and 
not  to  the  removal  of  the  gland.  Brown- Sequard 
repeated  and  extended  his  observations.  His  con- 
clusions are  shared  by  the  majority  of  physiologists 
to-day.  Even  his  claim  that  partial  extirpation 
does  not  as  a  rule  result  in  death  has  been  amply 
verified.  In  his  over-enthusiasm — and  Brown- 
Sequard  was  a  most  enthusiastic  gentleman — he 
declared  that  the  adrenals  were  even  more  impor- 
tant to  well-being  than  the  kidneys  themselves. 

Not  the  least  remarkable  thing  to  be  noticed  in 
these  extirpation  experiments  is  the  way  the  ani- 
mal will  appear  quite  normal  for  some  time  after 
the  operation,  and  then  quite  suddenly  begin  to 
exhibit  effects.  Let  us  illustrate  this  by  giving  the 
protocol  in  the  case  of  a  female  Macacus  monkey, 
whose  adrenals  were  removed  by  Dr.  Kahn  ( quoted 


THE  ADKENAL  GLANDS  73 

by  Mathews).  The  animal  weighed  a  little  over 
four  pounds  and  fed  on  fruit.  "Right  suprarenal 
removed  under  ether  Nov.  9,  1911.  The  wound 
heals  quickly.  On  4  December,  25  days  after  the 
operation,  when  the  weight  was  62  ounces,  took  out 
the  left  suprarenal.  On  the  fifth  the  animal  is  very 
well  and  eats  heartily.  On  the  sixth  she  eats  with 
normal  appetite.  Is  active.  There  is  a  little  edema 
(swelling)  at  the  edges  of  the  wound.  On  the 
seventh,  normal.  On  the  eighth,  normal,  but  appe- 
tite a  little  less.  On  the  ninth  at  9  a.m.  is  fairly 
weak,  lies  stretched  out  on  the  bottom  of  the  cage ; 
no  appetite;  wound  in  best  state.  At  9:12  a.m. 
great  increase  in  prostration.  Apathetic.  The  eyes 
are  open  and  look  about.  At  1:45  p.m.,  being 
nearly  moribund,  was  killed  with  chloroform.  The 
liver  was  examined  for  glycogen ;  only  a  trace  was 
found.  The  animal  lived  five  days.  For  four  days 
it  could  not  be  told  from  a  normal  animal.  The 
sudden  onset  of  the  symptoms  of  extreme  depres- 
sion has  the  appearance  of  an  intoxication." 

Why  the  "normalcy"  for  some  days  after  the 
operation,  and  then  the  sudden  change  for  the 
worse,  is  not  at  all  clear.  Perhaps  the  body  has 
a  hormone  reserve  that  holds  out  for  four  days 
and  then  gives  out. 

Addison's  disease. — The  equivalent — or  what  is 
supposed  to  be  the  equivalent — of  the  removal  of 
the  adrenals  may  be  seen  in  man  in  Addison's  dis- 


74        GLANDS  IN  HEALTH  AND  DISEASE 

ease.  Dr.  Addison  regarded  the  disease  as  "asthe- 
nia (loss  of  strength),  irritability  of  the  stomach 
and  change  of  color  in  the  skin."  In  a  recent 
(Feb.,  1921)  issue  of  the  New  York  Medical 
Journal,  Dr.  Eidelsberg  records  a  case;  let  us  see 
how  the  symptoms  agree  with  Addison's.  The  man, 
aged  30  years,  was  admitted  to  the  medical  ward 
of  the  Post-Graduate  Hospital,  complaining  of 
abdominal  pain,  vomiting,  and  weakness.  The  ill- 
ness began  suddenly  ten  days  previously.  There 
was  loss  of  appetite,  weakness,  vomiting  immedi- 
ately after  each  meal,  constant  pain  in  the  abdo- 
men, marked  constipation,  dizziness,  and  fainting 
sensation  on  slightest  exertion.  These  symptoms 
continued  throughout  the  entire  ten  days,  increas- 
ing in  severity.  The  patient  appeared  "tanned," 
as  though  he  had  exposed  himself  to  the  sun's  rays. 
There  were  about  15  small,  pale  scars  scattered  over 
his  body.  The  weakness  rapidly  increased  until 
the  patient  could  not  turn  in  bed.  The  vomiting 
grew  worse,  and  no  food  was  retained. 

On  the  evening  of  the  sixth  day  after  admission 
to  the  hospital,  the  patient  suddenly  became  un- 
conscious, his  pulse  became  imperceptible,  and  in 
five  minutes  he  ceased  to  breathe.  An  autopsy 
examination  revealed  that  both  suprarenals  were 
markedly  enlarged  and  soft,  and  on  cutting,  ap- 
peared, except  for  a  thin  cortical  portion,  to  con- 


THE  ADKENAL  GLANDS  75 

sist  of  a  soft,  cheesy  material.  Several  areas  typi- 
cal of  a  tuberculosis  lesion  were  found. 

The  "pigmentation"  is  usually  a  characteristic 
feature  of  the  disease.  Sometimes  it  is  absent,  and 
sometimes  it  is  present  in  diseases  other  than  Addi- 
son's.  Where  it  is  present  the  color  may  vary  any- 
where from  the  dark  hue  of  the  Negro  to  a  faint 
sunburn  brown.  Characteristic  also  of  Addison's 
disease  are  the  signs  of  muscular  weakness  (with 
no  corresponding  emaciation).  "The  patient  is 
very  easily  tired,  and  is  never  able  to  get  properly 
rested."  One  may  add  that  in  most  cases  the  blood 
pressure  is  very  low,  the  heart  feeble  in  action,  the 
temperature  is  usually  subnormal,  and  the  patient 
presents  an  anemic  appearance. 

The  marked  pigmentation  of  the  skin  in  Addi- 
son's  disease  is  supposed  to  be  due  to  a  disturbed 
relationship  between  adrenaline  and  melanin,  the 
characteristic  pigment  present  in  the  skin.  When 
the  adrenals  are  diseased  and  the  amount  of  adrena- 
line reduced  as  a  consequence,  the  factor  that  con- 
trols melanin  formation  is  removed,  and  an  excess 
of  the  skin  pigment  is  deposited. 

The  reader  will  notice  analogies  between  this 
theory  and  the  one  advocated  by  Cassan  more  than 
a  hundred  years  ago. 

Effect  of  adrenal  extract. — We  have  seen  that 
cases  of  hypothyroidism,  such  as  myxedema,  can 


76         GLANDS  IN  HEALTH  AND  DISEASE 

be  cured  by  administering  thyroid  extract;  can  we 
cure  an  analogous  disease  of  the  adrenals  by  the 
administration  of  adrenal  extract?  Can  we  re- 
lieve patients  suffering  from  Addison's  disease  by 
any  such  method?  We  have  already  indicated  that 
the  answer  must  be  in  the  negative.  We  can  supply 
no  good  reason  for  the  failure,  unless  we  assume 
that  the  adrenal  hormones,  unlike  the  thyroid  ones, 
are  quickly  destroyed  in  the  system ;  and  even  then 
a  veil  of  obscurity  still  overshadows  the  situation. 
We  must  remember  in  this  connection,  as  pointing 
to  how  far  from  a  complete  solution  we  really  are, 
that  the  most  characteristic  feature  of  Addison's 
disease,  the  pigmentation  of  the  skin,  has  never 
been  experimentally  produced. 

"Grafting." — From  what  has  been,  and  what  will 
be  said  on  the  subject  of  grafting  (see  more  par- 
ticularly Chapter  VI),  one  might  suppose  that  the 
use  of  such  a  method  would  be  an  improvement 
over  the  use  of  extracts.  If  the  graft  takes  and  a 
circulatory  system  is  set  up,  the  gland  ought  to 
behave  like  any  organ  of  the  body  that  is  "alive" 
and  that  functions  properly.  Theoretically  it 
ought  to  do  so;  in  practice  it  seldom  does.  Sur- 
geons in  the  late  war  have  shown  much  ingenuity 
in  grafting  pieces  of  skin;  occasionally  thyroid 
grafts  have  been  carried  out  successfully ;  but  when 
we  come  to  adrenal  grafting  we  can  record  little 
else  but  failure.  The  gland  atrophies  and  the  med- 


THE  ADRENAL  GLANDS  77 

ullary  portion  disappears  altogether.  Some  ex- 
perimenters have  recorded  temporary  successes, 
but  nothing  that  as  yet  warrants  much  optimism. 
Jaboulay,  a  French  surgeon,  transplanted  the 
adrenals  of  a  dog  into  a  patient  suffering  from 
Addison's  disease.  The  surgeon  does  not  tell  us 
what  happened  to  the  transplanted  gland,  but  he 
does  record  that  the  patient  died  within  24  hours! 
Dr.  Voronoff  might  reply  that  one  of  two  reasons 
would  explain  this :  either  the  surgeon  was  a  bun- 
gler and  did  not  perform  the  operation  skillfully 
enough;  or,  what  is  more  probable,  the  adrenal 
of  a  dog  cannot  replace  that  of  man.  Biology 
and  chemistry  certainly  have  taught  us  that 
"specificity"  is  a  distinguishing  feature  of  many 
dynamic  reactions.  In  any  case,  before  we  con- 
demn adrenal  grafting,  many  more  such  experi- 
ments will  have  to  be  performed. 

Hyper-adrenalism. — Neither  is  our  information 
less  obscure  with  regard  to  conditions  where  there 
is  an  excessive  production  of  the  adrenal  hormone 
— here  again  in  striking  contrast  to  our  knowledge 
of  hyper-thyroidism.  "The  whole  subject,"  writes 
Vincent,  an  eminent  English  authority,  "is  very 
obscure  and  requires  further  and  continuous  inves- 
tigation." 

The  cortex. — To  what  extent  our  ignorance  of  the 
entire  subject  of  the  adrenal  glands  is  due  to  our 
ignorance  of  the  part  played  by  the  cortex  of  the 


78        GLANDS  IN  HEALTH  AND  DISEASE 

gland,  it  would  be  hard  to  say.  You  will  remember 
that  at  the  beginning  of  the  chapter  we  stated  that 
the  gland  consists  of  two  very  distinct  portions, 
the  cortex  and  the  medulla.  The  latter,  as  we  shall 
wee,  contains  adrenaline,  the  best  known  of  all  the 
homiones,  and  indeed  a  very  important  substance. 
But  evidence  is  accumulating  to  show  that,  the 
medulla,  which  contains  this  hormone,  is  no  more 
important,  if  indeed  as  important,  to  life  than  is 
the  cortex,  which  does  not  contain  adrenaline. 
Biedl,  a  celebrated  Austrian  investigator,  claims 
to  have  succeeded  in  removing  the  cortex  from 
mammals,  leaving  behind  the  medulla  intact;  the 
animals  did  not-  survive.  This  leads  him  to  the 
view  that  the  cortex,  and  not  the  medulla,  is  the 
portion  of  the  organ  essential  to  life.  Schafer,  the 
Edinburgh  physiologist,  has  criticised  Kiedl's  con- 
clusions because  he  considers  it  impossible  to 
separate  completely  the  medulla  from  the  cortex. 
"I  think,"  he  writes,  "the  experience  of  most  people 
will  lead  them  to  believe  such  a  separation  impos- 
sible." Yet  the  view  docs  persist,  that  the  cortex, 
if  anything,  is  even  more  important  to  the  body 
than  the  medulla. 

What  hormone,  if  any,  the  cortex  contains,  is  not 
clear.  No  substance  corresponding  to  the  adrena- 
line of  the  medulla  has  been  isolated  from  it.  A 
theory  has,  however,  been  advanced  that  the  real 
seat  for  the  manufacture  of  adrenaline  is  the  cor- 


THE  ADRENAL  GLANDS  79 

tex;  that  the  hormone  is  there  made  from  tyrosine, 
one  of  the  best  known  of  our  amino-acids,  which 
in  turn  are  decomposition  products  of  proteins ;  * 
and  that  the  adrenaline,  once  formed,  is  passed  to 
the  medulla,  where  it  is  stored.  This  is  an  attrac- 
tive hypothesis,  but,  like  many  attractive  hy- 
potheses, lacks  experimental  proof. 

Another  view  of  the  function  of  the  cortex  is 
that  it  destroys  poisons — either  those  produced  in 
(he  course  of  body  metabolism,  due  perhaps  to 
muscular  activity  (theory  of  auto-intoxication),  or 
(hose  entering  the  body  from  the  outside.  Si  ill 
another  theory  is  the  one  that  stresses  the  close 
relationship  existing  between  the  cortex  on  the  one 
hand,  and  (lie  generative  glands  on  the  other.  It 
lias  been  said  thai  (he  enlargement  (hypertrophy) 
of  the  adrenal  gland  goes  hand  in  hand  with  pre- 
cocious development  of  the  reproductive  organs. 

The  medulla. — When  we  come  to  discuss  the 
function  of  the  medulla  we  are  on  much  firmer 
ground,  for  here  we  shall  see  we  have  a  tissue  that 
contains  a  substance  which  itself  induces  some  re- 
markable changes.  We  must  now  discuss  this  sub- 
sin  nee — adrenaline. 

Adrenaline.2 — The  most  significant  advance  made 
in  our  study  of  the  adrenals  is  the  isolation,  in  a 

1  Sec  tho  chapter  oft  Ammo-Acids  in  the  author's  book  on 
Vitaniinrs. 

a'llic  relation  of  adrenaline  to  the  nervous  system  is  reserved 
for  Chapter  XII. 


80        GLANDS  IN  HEALTH  AND  DISEASE 

chemically  pure  state,  of  one  of  its  hormones, 
.adrenaline.  This  substance  has  not  only  been  iso- 
lated from  the  gland,  but  it  has  also  been  synthe- 
sized in  the  laboratory.  The  organic  chemist  gives 
to  it  the  name  orthodioxy  phenyl-ethanol-methyla- 
mine,  and  he  knows  that  it  is  therefore  related  to 
tyrosine,  an  important  amino-acid  obtained  when 
proteins  are  decomposed.1  With  the  help  of  a  little 
fancy  and  a  little  fact,  the  physiological  chemist 
explains  the  indispensability  of  some  of  these 
amino-aeids  by  declaring  that  they  constitute  the 
raw  materials  for  the  manufacture  of  hormones. 

If  we  except  the  isolation  of  the  hormone  from 
the  thyroid,  the  isolation  of  adrenaline  remains  the 
only  case  on  record  of  the  extraction  of  a  hormone 
in  a  pure  condition  from  its  gland.  "It  is  one  of 
the  greatest  triumphs  of  physiological  chemistry," 
writes  Vincent,  "that  within  seven  years  of  the  dis- 
covery of  the  powerful  effects  of  extracts  of  the 
adrenal  medulla  by  Oliver  and  Schafer  (Schafer's 
discovery  was  made  in  1894),  the  active  principle 
was  obtained  in  crystalline  form,  and  that  five 
years  later  its  composition  has  been  so  completely 
ascertained  that  it  has  been  synthesized,  and  the 
pure  active  synthetic  products  can  be  obtained 
from  the  manufacturing  chemists." 

The  men  primarily  responsible  for  the  isolation 

'See  the  chapter  on  Ammo- Acids  in  the  author's  book  on 
Vitamines. 


THE  ADRENAL  GLANDS  81 

of  adrenaline  from  the  adrenals  are  von  Ftirth,  an 
Austrian;  Abel,  professor  at  Johns  Hopkins;  and 
Takamine,  a  Japanese  domiciled  in  the  United 
States.  Friedmann,  a  German,  succeeded  in  pro- 
ducing adrenaline  synthetically  in  the  chemist's 
laboratory.  While  it  is  not  my  intention  in  a 
volume  of  this  kind  to  enter  into  any  details  re- 
garding the  chemical  steps  involved  in  the  isola- 
tion of  hormones,  the  briefest  outline  of  Abel  and 
Takamine's  methods  for  isolating  adrenaline  from 
its  gland  will  be  given.  Even  though  such  an  out- 
line proves  too  "technical,"  it  can  hardly  be  omit- 
ted from  a  book  purporting  to  deal  with  hormone 
action. 

Preparation  of  adrenaline. — Very  concentrated 
adrenal  extracts  are  largely  freed  from  inactive 
substances  by  treatment  with  alcohol,  lead  acetate, 
etc.;  then  the  active  substance  is  precipitated  in 
microscopic  crystals  by  the  addition  of  concen- 
trated ammonia.  The  precipitate  is  then  purified 
by  repeatedly  dissolving  in  acid  and  reprecipitat- 
ing  with  ammonia.  The  resulting  prismatic  needles 
or  rhombic  plates  are  those  of  the  purified  or  iso- 
lated active  principle — adrenaline.1 

JFor  the  benefit  of  students  of  chemistry  who  may  read  this 
volume,  a  word  may  be  added  as  to  the  synthetic  production  of 
adrenaline.  This  may  be  obtained  by  the  action  of  methylamine 
upon  chloroaeetopyrocatechin : 

CCH3  ( OH )  aCOCH2C14-NH2CH3-»C^  ( OH )  a .  COCH, .  NHCH8 .  HC1 
The  methylamino  aceto-pyrocatechin  so  obtained  yields  adrena- 
line on  reduction. 


82        GLANDS  IN  HEALTH  AND  DISEASE 

Properties  of  adrenaline. — Before  entering  upon 
a  discussion  as  to  the  various  uses  that  adrenaline 
is  put  to,  it  may  be  said  that,  in  a  general  way, 
adrenaline  affects  the  body  tissues  in  much  the  way 
that  the  sympathetic  nervous  system  does.  By  way 
of  further  explanation  it  should  be  remarked  that 
the  nervous  apparatus  consists  of  two  sets  of  nerves 
connected,  to  be  sure,  and  yet  standing  out  apart 
from  each  other :  the  cerebro-spinal  system  and  the 
sympathetic  system.  The  former  is  made  up  of 
the  brain  and  the  spinal  cord  with  its  correspond- 
ing (cranial  and  spinal)  nerves;  the  latter  con- 
sists of  a  chain  of  nerve  cells  extending  on  each  side 
of  the  spinal  column,  connected  with  each  other  and 
with  the  spinal  nerves.  From  the  sympathetic  sys- 
tem, nerves  generate  that  follow  to  a  large  extent 
the  distribution  of  the  blood  vessels,  and  that  form 
large  networks  around  the  heart,  stomach,  etc. 
This  system  controls  the  internal  organs,  such  as 
the  heart,  the  blood  vessels,  kidneys,  etc.,  and  the 
sweat  glands  and  vessels  of  the  skin;  it  controls 
involuntary  muscular  movement,  and  is  related  to 

The  synthetic  adrenaline  is  optically  inactive, — that  is,  it  is 
the  d-l-  adrenaline;  whereas  that  obtained  from  the  adrenals  is 
the  optically  active  Z-adrenaline.  However,  not  only  has  the 
inactive  or  "racemic"  mixture  been  separated  into  its  active  com- 
ponents, but  the  interesting  fact  has  been  brought  out  by  Abder- 
halden  that  the  ^-adrenaline  is  about  15  times  as  strong  in  ita 
action  on  blood  pressure  as  the  d-adrenaline. 

For  a  fascinating  account  of  optically  active  substances,  the 
general  reader  can  do  no  better  than  read  Pasteur's  investigation 
of  tartaric  acid,  as  related  by  his  son-in-law,  Valery-Radot,  in 
his  book  dealing  with  the  life  of  that  immortal  French  scientist. 


THE  ADKENAL  GLANDS  83 


such  processes  as  contraction  and  dilation,  secre- 
tion, and  various  nutritional  processes. 

In  their  action  the  sympathetic  nerves  are  often 
antagonistic  to  the  cranial  ones.  The  stimulation 
of  the  latter  stops  the  heart  beat;  the  stimulation 
of  the  sympathetic  fibers  quickens  the  heart  beat. 
So,  indeed,  does  adrenaline :  its  action  is  to  quicken 
the  heart  beat. 

It  would  be  difficult  to  name  a  substance  used  in 
medicine  that  has  proved  of  greater  value  than 
adrenaline.  It  causes  a  contraction  of  the  arteries 
and  is  an  excellent  hemostatic, — that  is,  it  checks 
the  flow  of  blood.  In  shock  and  collapse,  often  fol- 
lowing surgical  operations,  the  procedure  adopted 
by  Crile,  the  well-known  Cleveland  surgeon,  of 
administering  adrenaline  solutions,  has  been  gen- 
erally adopted.  Though  we  know  little  as  to  the 
cause  and  nature  of  shock,1  we  do  know  that  in 
such  a  condition  the  arteries  contain  less  blood, 
and  the  veins  more  blood  than  usual.  Since  adrena- 
line constricts  the  arteries,  its  use  under  these  con- 
ditions provokes  attempts  on  the  part  of  the  body 
to  restore  equilibrium. 

The  suggestion  has  been  made  that  trench  life  in 
war  leads  to  depression  of  adrenal  activity,  and 
that  this  is  connected  with  the  clinical  picture  of 
shock  in  war.  We  shall  return  to  this  later. 

It  might  be  expected  that  cases  of  hemorrhage,. 

*For  further  information  see  Chapter  XII. 


84        GLANDS  IN  HEALTH  AND  DISEASE 

with  the  copious  loss  of  blood  that  accompanies 
them,  would  be  benefited  by  adrenaline  treatment. 
This  is  in  fact  true  of  many  such  cases.  Injection 
of  the  hormone  constricts  the  blood  vessels,  and,  as 
Professor  Cannon,  of  Harvard,  has  shown,  actu- 
ally hastens  the  formation  of  a  blood  clot,  which 
in  turn  acts  as  a  seal  to  any  further  escape  of  blood. 

The  extensive  use  of  adrenaline  in  conjunction 
with  a  local  anesthetic  dates  from  1903,  when 
Braun,  a  German  surgeon,  found  that  a  subcutane- 
ous injection  of  the  hormone  produces  a  bloodless 
or  bleached  area — of  great  importance  to  the  sur- 
geon in  giving  him  a  "clear  field  of  operation" — 
even  better  than  the  method  of  bandaging  or  freez- 
ing. Then,  as  a  further  incentive  to  its  use,  it  was 
shown  how,  applied  in  conjunction  with  cocaine  or 
novocaine,  the  effects  of  the  anesthetic  are  in- 
creased and  last  longer;  neither  are  there  such  un- 
pleasant after-effects.  Since  then  adrenaline  in 
conjunction  with  anesthetics  has  been  used  more 
and  more. 

One  may  cite  its  invariable  use  in  ophthalmolog- 
ical  surgery.  In  eye  operations  and  examinations 
the  application  of  adrenaline  has  opened  up  many 
new  possibilities. 

Since  we  are  on  the  subject  of  the  eye,  it  may  be 
of  interest  to  record  that  in  a  state  of  mental  dis- 
order which  goes  under  the  name  of  "dementia 
precox,"  it  has,  at  times,  been  found  possible  to 


THE  ADKENAL  GLANDS  85 

differentiate  this  disease  from  others  showing  cer- 
tain similarities  by  injecting  the  hormone  into  the 
membrane  that  lines  the  eyelid  and  covers  the  eye- 
ball (t'he  "conjunctiva") ;  after  a  few  minutes  there 
follows  a  ma»rked  dilatation  of  the  pupil  ("mid- 
riasis"),  provided  the  patient  has  true  "dementia 
precox." 

The  amount  of  adrenaline  used  in  these  opera- 
tions and  tests  is  ridiculously  small;  perhaps  as 
little  as  five  to  ten  drops  of  a  solution  containing 
one  part  of  hormone  to  1,000  parts  of  water. 
Small  as  such  a  quantity  is,  it  is  yet  strikingly 
effective.  What  is  true  of  adrenaline  seems  to  be 
true  of  all  hormones :  that  their  effect  is  altogether 
out  of  proportion  to  the  small  amounts  of  material 
used.  It  is  this  disproportion  between  amount  of 
material  used  and  the  profound  changes  brought 
about  by  such  a  quantity,  that  has  caused  investi- 
gators to  compare  hormones  with  vitamines  and 
enzymes.  What  connection  there  is  between  them 
remains  a  mystery. 

Adrenaline  in  blood. — We  know  that  even  under 
normal  conditions  the  blood  always  contains  a 
small  quantity  of  adrenaline — so  small,  indeed,  that 
it  has  been  estimated  at  one  part  in  500  million  of 
blood.  For  reasons  that  will  soon  be  apparent, 
much  attention  has  been  given  to  methods  for  the 
quantitative  determination  of  adrenaline.  It  must 
be  remembered  that  the  quantities  involved  are 


$6         GLANDS  IN  HEALTH  AND  DISEASE 

almost  infinitesimal  in  amount,  and  to  devise  not 
only  qualitative,  but  quantitative  methods  for  de- 
tecting such  amounts,  appears  to  be  a  problem 
beset  with  endless  difficulties.  Yet  what  seems  to 
approach  the  impossible  has  been  accomplished. 
In  this  connection  it  is  of  interest  to  note  that 
physiological  methods,  like  spectroscopic  methods 
in  many  cases,  and  the  electroscopic  method  in  the 
case  of  radium,  have  proved  themselves  more  deli- 
cate than  chemical  ones.  For  example,  Meltzer 
has  devised  a  physiological  procedure  which  de- 
pends upon  the  action  of  adrenaline  in  dilating  the 
pupil  of  the  enucleated  eye  of  a  frog;  and  claims 
that  a  strength  of  hormone  one  part  in  20  million 
can  be  detected.  Using  a  loop  of  intestine  and  re- 
cording how  its  movements  are  inhibited  by  adrena- 
line, is  said  to  be  so  delicate  as  to  detect  one  part 
of  hormone  in  400  million. 

The  best  chemical  method  so  far  devised  is  one 
based  on  colorimetric  comparisons,  due  to  Professor 
Folin,  of  Harvard.  It  depends  on  the  blue  color 
obtained  when  adrenaline  is  added  to  phosphotung- 
stic  acid.  This  blue  color  can  be  noticed  in  dilu- 
tions of  adrenaline  of  one  part  to  three  million. 

Adrenaline  and  sugar  metabolism. — The  relation 
of  adrenaline  to  sugar  metabolism  will  be  referred 
to  in  Chapter  VII.  Here  it  should  be  said  that  the 
injection  of  this  substance  into  the  body  of  an  ani- 
mal increases  the  quantity  of  sugar  normally  found 


THE  ADKENAL  GLANDS  87 

in  blood,  and  may  give  rise  to  a  temporary  glyeo- 
suria  (sugar  in  the  urine) ,  which  is  a  form  of  what 
is  commonly  called  "diabetes."  It  will  be  shown 
that  the  pancreatic  hormone  acts  antagonistically 
to  the  adrenal  hormone,  thereby  helping  to  regulate 
body  equilibrium. 

Professor  Cannon  has  shown  that  an  increase  of 
adrenaline  in  the  blood  occurs  without  any  addition 
of  hormone  from  outside  sources  whenever  an  ani- 
mal gets  excited — for  example,  when  a  cat  gets 
ready  to  defend  itself  against  a  dog's  attack;  and 
also  that  such  an  increase  is  followed  by  a  hyper- 
glycemia  (an  increase  of  sugar  in  the  blood) .  This 
suggestion  that  the  adrenal  gland  is  involved  in 
emotional  outbursts  is  certainly  of  extraordinary 
interest.  The  fact  remains  too  that  when  a  cat  be- 
comes frightened  its  "pupils  dilate,  the  stomach  and 
intestines  are  inhibited,  the  heart  beats  rapidly, 
the  hairs  of  the  back  and  tail  stand  erect — all 
signs  of  nervous  discharges  along  the  sympathetic 
paths" ;  and  we  have  already  seen  how  similar  the 
action  of  adrenaline  and  the  stimulation  of  the 
sympathetic  fibers  are.1 

Summary. —  We  may  briefly  summarize  our 
knowledge  of  the  adrenals  by  stating  that  they  are 
unquestionably  essential  to  life,  though  conflicting 
theories  are  current  as  to  their  precise  function. 
Of  the  two  parts  into  which  the  adrenals  may  be 

1  See  further,  Chapter  XII. 


88        GLANDS  IN  HEALTH  AND  DISEASE 

divided,  the  cortex  and  the  medulla,  the  former,  if 
anything,  seems  to  be  more  essential  to  life  than 
the  latter,  though  so  far  no  one  has  succeeded  in 
showing  that  the  cortex  contains  any  specific  hor- 
mone. On  the  other  hand,  the  medulla  contains  the 
best  known  of  all  the  hormones,  adrenaline.  This 
hormone,  adrenaline,  has  not  only  been  isolated  in 
the  pure  state,  but  it  has  actually  been  synthesized 
in  the  laboratory.  Adrenaline  has  already  taken 
its  place  among  the  most  valuable  drugs  in  medi- 
cine. 


CHAPTER  VI 

THE   ORGANS   OF   REPRODUCTION 

We  have  convincing  evidence  that  the  organs  of 
reproduction,  or  the  "sexual"  glands,  produce  both 
an  external *  and  an  internal  secretion ;  in  this  re- 
spect showing  a  similarity  to  the  pancreas  and  the 
small  intestine.  The  external  secretion  contributes 
to  the  reproduction  of  the  species;  the  internal 
secretion — like  the  secretions  from  the  other  duct- 
less glands  that  we  have  studied,  contributes  to  the 
molding  of  the  species.  In  this  chapter  we  are,  of 
course,  primarily  interested  in  the  internal  secre- 
tion of  the  sexual  glands,  though  the  two  secretions 
cannot  always  be  sharply  separated. 

Proof  of  an  internal  secretion. — The  removal  of 
the  testes  or  ovaries,  an  operation  commonly  known 
as  "castration,"  if  carried  out  before  puberty,  pre- 
vents the  development  of  "secondary  sex  character- 
istics." In  the  female  the  periodic  act  of  menstrua- 
tion from  a  very  early  age  until  perhaps  her  fiftieth 
year,  is  indicative  of  a  .functional  ovary.  The 

1Some  physiologists  are  opposed  to  regarding  the  external 
secrefion  of  the  reproductive  system  as  a  true  secretion,  on  the 
ground  that  the  active  constituents  are  not  enzymes. 

89 


SO        GLANDS  IN  HEALTH  AND  DISEASE 

"coming  on  of  heat"  or  "rut"  in  animals  seems  to 
be  related  to  menstruation  in  human  females.  Now 
it  is  a  remarkable  fact  that  this  "rut"  is  no  longer 
noticed  upon  the  extirpation  of  the  ovary,  but  is 
again  brought  on  by  the  transplantation  to  another 
part  of  the  body  of  the  ovary  belonging  to  a  similar 
animal.  From  what  has  already  been  said  on  the 
subject  of  transplantation,  it  must  be  perfectly  evi- 
dent that  an  experiment  of  this  kind  admits  of  but 
one  conclusion :  that  the  nervous  mechanism  plays 
but  a  secondary  part,  if  it  plays  a  part  at  all ;  but 
that  on  the  other  hand,  the  ovary  must  discharge 
into  the  blood  some  substance  or  substances  which 
give  rise  to  the  phenomenon  in  question.  This,  of 
course,  means  that  the  ovary,  in  addition  to  giving 
rise  to  an  external  secretion  in  the  form  of  ova, 
that  contributes  to  the  reproduction  of  the  species, 
must  be  the  seat  of  an  internal  secretion. 

We  now  know  that  the  two  types  of  secretion  are 
produced  by  two  different  types  of  cells.  The  in- 
ternal secretion  is  developed  by  the  so-called  "in- 
terstitial cells,"  the  name  of  which  has  become  fa- 
miliar to  the  lay  reader  ever  since  topics  on  reju- 
venation have  become  popular  with  newspaper 
editors.  These  cells  lie  altogether  outside  of  the 
tubes  that  are  responsible  for  the  flow  of  the  ex- 
ternal secretion.  It  is,  in  fact,  possible  to  tie  the 
tube  that,  in  the  male,  connects  the  testes  with  the 
ejaculatory  tube  (the  "vas  deferens"),  thereby 


THE  OEGANS  OF  REPRODUCTION          91 

causing  the  sexual  elements  to  disappear;  yet  the 
interstitial  cells  not  only  are  left,  but  actually  in- 
crease in  number.  And  what  is  far  more  remark- 
able, the  sexual  instincts  remain  as  strong  as  ever. 
This  is  therefore  further  evidence  in  favor  of  the 
view  that  puberty  is  dependent  not  upon  the  pres- 
ence of  the  reproductive  elements,  but  rather  upon 
the  production  of  an  internal  secretion  due  to  in- 
terstitial cells. 

Brown-Sequard. — In  1889  Brown-Sequard,  one- 
time professor  at  Harvard,  and  later  professor  at 
the  College  de  France  in  Paris,  presented  a  paper 
before  the  Academic  de  Medecine  that  created  a 
sensation.  He  described  experiments  in  which  he 
had  himself  injected  with  extracts  obtained  from 
the  sexual  organs  of  a  ram;  the  result  was  that  he 
had  become  quite  "rejuvenated."  Despite  his 
seventy  years  he  felt,  he  said,  like  a  youth,  with 
all  a  youth's  vigor.  The  newspapers,  quite  justi- 
fiably, gave  much  prominence  to  this  get-young- 
quick  method,  and  for  a  short  time  Brown-Sequard 
was  an  international  hero.  Then  came  cries  from 
opposition  forces.  The  experiments  were  repeated 
and  nothing  like  what  was  alleged  by  the  French- 
American  could  be  discovered.  Brown-Sequard 
answered  his  critics  by  charging  that  his  technique 
had  not  been  followed  with  sufficient  care.  But 
his  replies  did  not  satisfy  the  critics ;  they  attacked 
him  mercilessly,  and  continued  the  attack  until  the 


93        GLANDS  IN  HEALTH  AND  DISEASE 

one-time  famous  physiologist  became  a  thoroughly 
discredited  man.  We  shall  presently  have  occasion 
to  discuss  the  objections  that  may  be  advanced  to 
the  use  of  testicular  extracts;  but  it  is  only  bare 
justice  to  the  memory  of  an  illustrious  man  of  sci- 
ence to  point  out  at  once  and  emphatically  that 
Brown- Sequard  seized  upon  the  germ  of  a  great 
discovery,  and  one  which,  even  to-day,  is  but  dimly 
perceived.  Moreover,  he  was  the  first  one  to  per- 
ceive clearly  the  intimate  relation  that  exists  be- 
tween the  various  organs,  due  to  their  internal 
secretions. 

He  writes:  "Each  tissue,  and,  more  generally, 
each  cell  of  the  organism,  secretes  for  its  own  use 
special  products  which  are  poured  into  the  blood 
and  which  influence,  through  the  intermediary 
agency  of  this  liquid,  and  not  through  the  mecha- 
nism of  the  nervous  system,  all  the  other  cells,  thus 
rendering  all  of  them  mutually  interdependent." 
To  say  that  each  tissue  and  each  cell  plays  such  a 
part  may,  or  may  not  be  the  entire  truth;  but  we 
have  here  a  wonderfully  clear  presentation  of  the 
functions  of  hormones. 

We  shall  see  presently  how,  in  the  hands  of 
Steinach,  Voronoff,  and  others,  the  Brown- Sequard 
view  was  adopted  and  extended.  In  the  meantime 
we  must  take  a  step  backward  and  examine  in 
more  detail  the  effects  of  castration.  You  will  re- 
member that  this  type  of  approach  to  the  subject 


THE  ORGANS  OF  REPRODUCTION          93 

is  the  one  that  so  often  yields  valuable  clues  as  to 
the  function  of  any  particular  part  of  the  organism. 

Castration. — Here  the  history  of  mankind  sup- 
plies us  with  an  abundance  of  material — at  least, 
in  so  far  as  the  male  part  of  the  population  is  con- 
cerned ;  for  our  information  concerning  the  female 
portion  is  slender.  Castration  was  extensively 
practised  in  antiquity,  and  still  is  in  oriental 
countries  where  there  are  watchers  of  the  harem. 
Professor  Falta  informs  us  that  it  was  carried  out 
in  Italy  "for  musical  purposes,"  and  that  the  prac- 
tice ceased  only  recently.  In  Eussia  a  religious 
sect  known  as  the  "skopzen"  include  castration  as 
a  necessary  part  of  their  religious  ritual.  Perhaps 
the  most  pathetic  account  that  has  been  handed 
down  to  us  is  that  of  the  famous  Abelard,  who  was 
castrated  by  order  of  Heloise's  uncle,  Fulbert. 

The  results  of  castration  are  much  dependent 
upon  the  age  at  which  it  is  performed.  If  this  is 
done  before  puberty,  the  sexual  instinct  disappears, 
never  to  return.  The  eunuch  often  grows  to  be  very 
tall,  those  reaching  six  feet  eight  inches  being 
common.  The  voice,  due  to  the  non-development 
of  the  larynx,  retains  the  sound  of  a  childish  so- 
prano. The  face  is  livid,  the  skin  poor  in  pigment 
and  the  flesh  flabby.  Very  often  the  breasts  are 
abnormally  developed,  and  almost  always  such  in- 
dividuals are  beardless.  These  last  two  symptoms 
have  often  been  taken  as  an  indication  of  the  devel- 


94         GLANDS  IN  HEALTH  AND  DISEASE 

opment  of  female  characteristics,  and  as  showing 
that  the  sex  characters  owe  their  presence  to  the 
genital  organs.  The  very  name  suggests  that  the 
sexual  organs  are  involved  in  the  development  of 
sex  characters ;  but  why  when  such  organs  of  a  male 
are  cut  out  of  his  system  he  should  then  tend  to 
revert  to  the  female  type  is  not  clear.  The  view 
is  gaining  ground  that  castration  produces  a 
"neutral"  rather  than  a  female  variety. 

What  effect  castration  has  upon  mental  develop- 
ment is  not  beyond  dispute.  From  the  accounts  of 
some  eunuchs  that  have  come  down  to  us,  who  at- 
tained distinction  in  their  day,  it  would  seem  as  if 
the  mind  of  the  person  is  not  affected.  Unfortu- 
nately our  information  as  to  their  age  at  the  time 
of  castration,  and  as  to  the  completeness  of  the 
operation,  is  meager;  and  both  these  factors  need 
to  be  known  before  we  pass  judgment.  Experi- 
ments with  animals  have  shown  that  castrated 
animals  lack  the  courage,  the  animation  and  the 
passions  of  normal  male  animals;  and  many  ob- 
servations on  eunuchs  lead  to  the  belief  that  there 
is  a  distinct  tendency  towards  the  suppression 
of  the  finer  emotions,  these  in  turn  being  sup- 
planted by  a  general  air  of  indifference  and  mental 
inertia. 

The  absence  of  certain  sex  characteristics — wThich 
does  not  always  imply  the  formation  of  sex  charac- 
ters belonging  to  the  opposite  sex — after  castration 


THE  ORGANS  OF  REPRODUCTION          95 


is  also  noticeable  in  animals.  Thus  stags  when 
castrated  young  do  not  develop  antlers;  and  even 
if  the  operation  is  performed  after  the  antlers  have 
appeared,  the  animals  no  longer  shed  them  annu- 
ally. If  horns  are  on  they  fall  off.  This  is  true  of 
sheep.  The  cock  loses  its  plumage,  its  wattles  and 
its  characteristic  male  type  of  voice. 

The  records  of  castration  in  the  female  are 
meager.  The  operation  is  rarely  performed  before 
puberty,  and  after  this  stage  has  been  reached,  the 
changes  are  not  so  marked.  This  applies  also  to 
domestic  animals.  The  few  experiments  that  have 
been  performed  make  it  seem  likely  that  one  of 
the  functions  of  the  female  genital  organs  is  to 
suppress  a  tendency  to  revert  to  the  male  type;  in 
their  absence  the  duck  and  pheasant,  for  example, 
assume  male  plumage. 

In  both  the  male  and  female,  whether  man  or  ani- 
mal, castration  is  followed  by  an  accumulation  of 
fat  in  the  body,  making  it  appear  that  the  general 
metabolism  of  the  system  has  been  disturbed. 

The  results  of  castration  can  be  observed  in  those 
persons  whose  sexual  organs  have  for  one  reason 
or  another  not  developed  normally.  Professor 
Tandler  refers  to  such  "eunuchoids"  as  "tall,  or  if 
complications  are  absent,  at  least  not  stunted  in 
growth;  they  show  the  typical  fat  distribution  of 
eunuchs.  The  skeletal  dimensions  are  character- 
ized by  an  especial  length  of  extremities.  There 


96         GLANDS  IN  HEALTH  AND  DISEASE 

is  a  more  or  less  pronounced  disturbance  of  the 
development  of  the  genitalia,  with  faulty  develop- 
ment of  secondary  sex  characteristics.  It  is  prob- 
able that  in  such  cases  we  have  to  do  with  a  de- 
velopmental disturbance  beginning  primarily  in 
the  sexual  glands,  and  indeed  the  interstitial 
glands,  as  functional  disturbances  of  the  generative 
glands  alone  do  not  lead  to  eunuchoidism." 

The  last  statement  receives  support  from  experi- 
ments already  described,  wherein  the  reproductive 
elements  were  suppressed,  yet  the  gland  consist- 
ing of  the  interstitial  cells  thrived,  and  the  several 
sex  characteristics  were  retained;  also  where  a 
tumor  arises  that  interferes  with  the  supply  of  the 
reproductive  elements,  yet  does  not  attack  the  inter- 
stitial cells,  we  may  get  a  similar  result.  On  the 
other  hand,  where  the  interstitial  cells  themselves 
are  affected,  the  clinical  picture  obtained  represents 
that  of  castration ;  which  in  itself  suggests  that  the 
primary  results  of  castration  are  probably  due  to 
the  absence  of  a  hormone  which  is  normally  elabo- 
rated by  the  interstitial  cells. 

Further  confirmation  of  the  views  just  advanced 
is  obtained  from  X-ray  studies.  These  rays  have 
a  selective  action  in  the  sense  that  they  destroy 
the  cells  of  the  testes,  yet  not  those  belonging  to 
the  interstitial  gland.  If  the  testicles  of  a  roebuck 
are  exposed  to  X-rays,  the  antlers  do  not  undergo 
any  alteration;  here  the  generative  cells  proper 


., 


THE  ORGANS  OF  REPRODUCTION  97 


,ve  been  destroyed.  When  the  animal  is  cas- 
trated, which  involves  removal  both  of  the  external 
and  internal  glands,  it  loses  its  antlers.  Clearly 
then  the  result  of  castration  must  be  attributed 
to  the  loss  of  the  interstitial  hormone. 

From  the  evidence  presented  we  may  conclude 
that  the  hormone  or  hormones  that  give  rise  to  the 
male  characteristics  are  due  to  the  interstitial 
gland.  The  hormone  is  elaborated  by  the  gland  and 
passes  directly  into  the  blood  stream.  We  are  here 
therefore  dealing  with  a  gland  belonging  to  the 
"ductless"  group. 

Professor  Biedl  says  that  "it  is  highly  probable 
that,  by  the  agency  of  its  secretory  product,  the 
interstitial  gland  is  responsible  for  the  develop- 
ment of  the  male  sexual  gland  from  the  indifferent 
genital  trace.  That  it  has  a  determining  influence 
upon  the  normal  development  and  maturity  of  the 
generative  portion  of  the  sexual  gland,  upon  the 
formation  of  the  secondary  genital  organs,  and 
upon  the  existence  and  persistence  of  those  morpho- 
logical and  biological  characters  which  are  the 
property  of  the  male  sex,  is  undoubted." 

Our  information  regarding  the  interstitial  cells 
of  the  female  is  meager,  but  whatever  we  do  know 
points  to  their  presence,  and  to  their  possessing  a 
function  similar  to  the  cells  of  the  male. 

Grafting. — Brown- Sequard's  suggestion  that  the 
active  genital  glands  impart  vigor  to  the  body,  due 


98         GLANDS  IN  HEALTH  AND  DISEASE 

to  the  elaboration  of  an  internal  secretion,  and  the 
further  fact  that  with  old  age  the  interstitial  cells 
become  fewer  and  smaller,  must  have  suggested  to 
physiologists  a  possible  connection  between  old  age 
and  the  interstitial  glands.  To  test  out  such  a 
possibility  has  led  to  a  number  of  extremely  inter- 
esting experiments.  Kesearch  workers  following 
Brown-S£quard  showed  that  the  addition  to  the 
food,  or  the  injection  into  the  blood,  of  testicular 
extracts,  failed  to  change  castrated  into  normal 
animals,  or  old  animals  into  young  ones.  The  rea- 
son for  this  is  not  easy  to  give,  unless  we  assume 
that  a  chemical  process  involving  an  extraction  of 
the  hormone  from  the  interstitial  gland — an  opera- 
tion which  is  usually  carried  out  by  triturating  the 
gland  with  sand  and  water,  filtering  and  using  the 
filtrate — causes  an  alteration  of  the  hormone. 

Dr.  Voronoff  remarks  that  "the  injections  of 
testicular  juice  have  not  had  the  result  which 
Brown-S£quard  expected  from  them,  because  the 
glandular  extracts  undergo  rapid  changes,  do  not 
contain  the  whole  of  the  product  of  the  internal  se- 
cretion, and  are  even,  at  times,  toxic."  *  This  is 
obviously  not  true  of  some  of  the  other  ductless 
glands,  notably  the  thyroid. 

Next  came  the  suggestion  that  a  much  better 
method  than  that  of  injection  of  gland  would  be  the 

*See  Life  by  Serge  Voronoff.    E.  P.  Dutton  &  Company,  New 
York. 


THE  ORGANS  OF  REPRODUCTION  99 

grafting  of  a  new  tissue  to  take  the  place  of  the 
old.  This  held  out  hope,  for  many  experiments 
with  glands  of  the  ductless  variety  pointed  to  the 
fact  that  they  could  be  removed  from  their  original 
positions  in  the  body  and  grafted  on  to  some  distant 
tissue  of  the  body,  with  no  ill-effects,  provided  the 
graft  "took" ;  that  is,  provided  a  healing  condition 
set  in  whereby  the  blood  vessels  of  the  gland  and 
those  of  the  rest  of  the  body  would  connect  up,  so 
as  to  allow  the  hormone  of  the  ductless  gland  to 
enter  the  general  circulation. 

Upon  ideas  such  as  these  are  based  the  much- 
talked-of  experiments  of  a  Steinach  and  a  Voronoff. 
"The  grafting  of  a  young  sex  gland  in  full  activity," 
writes  Dr.  Voronoff,  "means  incorporating  in  the 
organism  the  very  source  of  our  organic  action. 
Thus  the  body  would  be  supplied  not  with  a  dead 
product,  incomplete,  often  changed,  introduced 
from  time  to  time  by  means  of  subcutaneous  injec- 
tions, but  a  living  organ  carrying  out  its  functions 
itself.  To  graft  this  gland  is  to  place  it  in  direct 
communication  with  our  blood  vessels,  which  will 
undertake  to  transport  the  precious  fluid  in  pro- 
portion to  its  formation  in  the  intimacy  of  our 
tissues." 

Before  we  proceed  to  these  experiments  a  word 
must  be  said  as  to  the  methods  used  in  the  trans- 
planation  of  tissues.  There  are  two  ways  of  doing 
this:  either  by  merely  inserting  a  small  strip  of 


100      GLANDS  IN  HEALTH  AND  DISEASE 

tissue  in  the  desired  place,  or  by  first  carefully 
connecting  the  engrafted  with  the  main  tissue  by 
stitching  suitable  blood  vessels  together.  In  the 
first  case  general  circulation  in  the  engrafted  tissue 
is  for  a  time  delayed;  in  the  second,  it  is  immedi- 
ately set  up.  The  first  method  has  been  exten- 
sively used  in  replacing  small  portions  of  skin  in 
burns.  It  has  even  been  employed,  and  with  suc- 
cess, to  interchange  the  ovaries  in  hens,  and  to  re- 
place the  thyroid  and  parathyroid.  The  second 
method,  more  difficult  to  execute,  has  the  advantage 
in  that  the  transplanted  tissue  may  be  of  much 
larger  size.  By  this  method  the  kidney,  the  spleen, 
and  even  a  limb  have  been  transferred  from  one 
dog  to  another ;  and  segments  of  arteries  that  have 
been  kept  in  cold  storage,  or  preserved  in  formalde- 
hyde, have  successfully  replaced  portions  that  had 
been  removed  from  their  positions  in  the  body. 

It  should  be  pointed  out  that,  as  a  rule,  trans- 
plantation is  successful  only  if  tissues  of  the  same 
species  are  used,  though  experiments  have  shown 
that  the  arteries  of  a  dog  can  be  transplanted  to  a 
cat;  and  that  further,  much  of  the  work  recorded 
has  been  done  on  animals  rather  than  on  human 
beings.  In  the  hands  of  Carrel  and  other  famous 
surgeons  active  in  the  late  war,  the  art  of  grafting 
has  made  long  strides.  The  French  doctors  have 
proved  themselves  particularly  skillful  in  the  art. 

The  famous  Siamese  twins  illustrate  a  perfect 


THE  OEGAJSTS  OF  REPRODUCTION         101 

graft  for  which  Nature  is  responsible.  Here  the 
circulatory  system  resembled  that  of  one  rather 
than  of  two  beings.  An  imitation  of  this  kind  has 
been  produced  in  white  rats  by  opening  up  the 
membrane  enclosing  the  abdomen  and  stitching  the 
skin  and  connective  tissues  together. 

Steinach's  contribution. — In  approaching  the 
work  of  Steinach  and  others  we  must  be  more  than 
ever  careful  to  distinguish  fact  from  fancy;  to  re- 
late actual  experiments  without  drawing  fanciful 
conclusions  from  them.  Professor  Steinach,  one 
of  the  best  known  among  the  workers  on  the  func- 
tions of  the  sex  glands,  is  a  member  of  the  Vienna 
Academy  of  Sciences,  and  Director  of  its  Biological 
Institute.  His  work  as  a  biologist  has  commanded 
the  respect  and  admiration  of  his  colleagues 
throughout  the  world,  though  some  of  his  interpre- 
tations of  his  work  have  not  gone  unchallenged. 

These  prefatory  remarks  are  necessary  because 
the  impression  seems  to  have  gained  ground  that 
he  is  one  of  many  quacks  that  fatten  on  the  public's 
credulity.  Such,  in  fact,  was  the  impression 
gained  by  many  newspaper  readers  after  hearing  of 
the  sudden  death  of  a  rich  Australian,  who  was  to 
deliver  a  public  lecture  in  London  on  "How  I  was 
made  twenty  years  younger  by  the  method  of  Dr. 
Steinach,"  and  who  died  under  somewhat  mysteri- 
ous circumstances  on  the  very  eve  of  the  lecture. 
The  newspaper  drew  the  moral  of  St.  Mark  that 


102       GLANDS  IN  HEALTH  AND  DISEASE 

new  wine  should  not  be  poured  into  old  bottles! 

Prior  to  1910,  when  Dr.  Steinach  published  the 
first  of  his  experiments,  it  had  already  been  known 
that  the  generative  apparatus  consists  of  an  inter- 
nal and  external  secretion,  and  there  were  even 
then  indications  that  the  hormone,  or  hormones, 
produced  by  the  internal  secretion  (in  the  inter- 
stitial cells)  controlled  sex  characteristics.  Pro- 
fessor Steinach  wished  first  to  convince  himself 
that  what  was  generally  believed  had  foundation 
in  fact:  that  the  internal  secretion  actually  con- 
trolled sex  characters.  With  this  in  view  he  cas- 
trated a  number  of  male  rats  and  guinea-pigs  and 
planted  ovaries  under  the  skin.  The  animals  de- 
veloped marked  feminine  features:  their  breasts 
and  nipples  increased  in  size  and  they  were  sought 
by  the  males.  Previous  experiments  on  the  trans- 
plantation of  the  testes  had  shown  that  though  the 
reproductive  glands  proper  decayed  and  the  inter- 
stitial glands  did  not,  yet  the  sex  desire  remained. 
These  experiments  indicated  two  things :  first,  that 
the  generative  glands  have  much  to  do  with  deter- 
mining the  sex  of  the  animal;  secondly,  that  the 
portion  of  the  glands  particularly  responsible  is 
the  interstitial  gland. 

Old  age. — As  already  pointed  out,  the  work  of 
Brown- Sequard  suggested  a  connection  between 
the  decay  of  the  genital  glands  and  the  onset  of  old 
age.  This  was  the  next  problem  that  Steinach  set 


THE  OEGANS  OF  KEPEODUCTION         103 

himself  to  elucidate.  His  idea  was  to  transplant 
the  sexual  glands  of  young  rats  to  the  system  of 
old  ones — to  put  "new  wine  into  old  bottles." 
Much  preliminary  work  was  necessary  in  order  to 
determine  the  conditions  for  developing  healthy 
breeds  of  rats.  The  extensive  vitamine  studies,  in 
which  rats  are  very  largely  employed,  had  then 
hardly  begun ;  otherwise  such  difficulties  could  have 
been  avoided.  Steinach  succeeded  not  only  in  im- 
proving the  general  condition  of  the  old  rats,  not 
only  in  renewing  the  sex  instinct,  but  actually  in 
prolonging  the  life  of  the  animal.  "Three  weeks 
after  the  operation  the  whole  behavior  changed* 
the  rat  (an  old  one)  began  to  keep  its  head  erect, 
came  forward  from  its  hole,  paid  a  lively  interest 
toward  the  outer  world,  and  its  hair  began  to 
grow  smooth  and  shiny.  When  another  male  rat 
had  been  let  into  its  cage  it  attacked  him  immedi- 
ately, and  when  a  female  rat  was  let  in,  it  eagerly 
performed  the  sexual  function,  and  as  only  one 
vas  deferens  (see  subsequent  paragraph)  was  li- 
gated,  the  coitus  was  successful.  The  young  of  the 
female  fecundated  by  the  rejuvenated  rats  thrived 
well,  and  propagated  further." 

Our  discussion  of  the  interstitial  glands  has  al- 
ready shown  that  in  the  investigations  of  this  duct- 
less gland,  one  of  three  methods  in  operating  tech- 
nique may  be  employed :  the  duct  from  the  testicle 
connecting  the  testis  with  the  ejaculatory  tube 


104       GLANDS  IN  HEALTH  AND  DISEASE 

(the  vas  deferens)  is  cut  off,  thereby  stopping  the 
production  of  the  external  secretion,  and  hence  the 
production  of  the  reproductive  elements;  or  the 
genital  glands  are  submitted  to  the  effects  of 
X-rays,  causing  the  less  resistive  reproductive  ele- 
ments to  be  destroyed.  In  either  case  the  inter- 
stitial cells  are  not  only  left  intact,  but  actually 
multiply  and  produce  hormone  in  quantity  (and 
quality?)  sufficient  to  rejuvenate  (?)  the  organism. 
There  is  still  a  third  method,  and  that  is  to  trans- 
plant the  gland  from  a  vigorous  animal  to  the  one 
under  experimentation.  We  have  already  pointed 
out  that  the  transplantation  of  testicles  has  shown 
that  under  such  conditions,  the  reproductive  ele- 
ments disappear,  but  the  interstitial  cells  continue 
to  thrive.  Here  again  the  organism  is  favorably 
affected. 

All  three  methods  point  to  the  interstitial  gland 
as  the  source  from  which  rejuvenation  springs. 

With  Steinach  the  question  now  arose  as  to  which 
of  the  three  methods  would  be  the  one  best  adapted 
for  his  purpose.  In  his  experiments  with  human 
beings  he  decided  upon  the  first  one — the  ligature 
of  the  vas  deferens — as  being  the  simplest  to  per- 
form, and  the  one  least  likely  to  give  rise  to  unfa- 
vorable post-operative  symptoms.  "By  stimulat- 
ing the  action  of  the  interstitial  gland  at  the  ex- 
pense of  the  generative  function,  it  is  Steinach's 
idea  to  bring  about  a  rejuvenation  process  in  older 


THE  ORGANS  OF  REPRODUCTION"    105 

people  by  the  resuscitation  and  renewal  of  the 
weakening  secondary  characters."  We  shall  see 
that  Dr.  Voronoff  selected  the  more  difficult  graft- 
ing procedure. 

"The  operation  is  a  very  simple  one,"  writes  Dr. 
Steinach;  "absolutely  painless.  Quite  free  of  any 
risk  whatever.  Takes  no  longer  than  fifteen  min- 
utes to  perform.  Seven  to  ten  days  in  the  hospital 
are  all  that's  needed  afterwards.  But  the  opera- 
tion must  be  performed  with  minute  precision ;  and 
for  that  reason  I  cannot  guarantee  results  unless 
I  am  personally  present." 

With  the  help  of  a  local  anesthetic  a  small  in- 
cision is  made  and  the  vas  deferens  tied  and  cut  off. 
Care  is  taken  not  to  injure  the  blood  vessels  near 
by.  The  result  is  that  the  seminal  vesicle  (either 
one  of  the  two  reservoirs  for  the  semen)  and  the 
interstitial  gland  are  completely  cut  off  from  one 
another ;  and  this  in  turn  gives  rise  to  a  multiplica- 
tion of  the  interstitial  cells,  and  to  an  increase  of 
the  hormone  produced  by  them. 

Professor  Steinach  has  performed  the  operation 
on  men  on  several  occasions.  In  some  instances 
these  men  were  fairly  young  but  physically  weak; 
in  others,  the  subjects  were  senile  men.  "The  ap- 
pearance of  the  subjects  became  youngish,  fresh, 
their  bodily  strength  increased,  the  tremor  of  their 
hand  disappeared,  memory  and  will  power  re- 
turned, and  the  sexual  power  was  restored." 


106       GLANDS  IN  HEALTH  AND  DISEASE 

Dr.  Steinach  has  not  had  the  same  success  with 
females  as  with  males.  With  females  the  X-ray 
method  holds  out  the  most  hope,  but  even  with  this 
method  the  results  have  not  been  very  encouraging. 
Just  why  this  should  be  so  is  not  clear. 

Of  the  cases  described,  one  may  be  quoted  as 
typical.  "He  was  71  years  of  age,  controller  of  a 
large  business.  The  man  was  actually  ill,  and 
showed  the  usual  signs  of  old  age  and  decay,  such 
as  dizziness,  poor  breathing,  heart  weakness, 
shakiness  and  intense  fatigue.  For  eight  years 
ambition  had  been  practically  non-existent.  Some 
months  after  the  operation  there  was  remarkable 
evidence  that  the  conditions  of  senility  had  been 
checked.  The  man's  power  came  back.  It  is  still 
increasing.  We  got  a  letter  from  him  recently 
(Dec.,  1919)  in  which  he  told  us  of  the  extraor- 
dinary change  that  had  taken  place  in  his  condi- 
tion. His  appetite  had  come  back.  His  old-time 
spells  of  depression  had  given  way  to  a  new  joy  in 
life.  He  had  become  fresh  in  looks  and  elastic  in 
body.  His  dizziness  had  gone.  His  hand  had  be- 
come firm  again.  He  specially  mentioned  the  fact 
that  he  was  again  able  to  think  clearly,  as  in 
earlier  years,  and  that  his  memory  had  greatly 
improved.  Also,  that  whereas  in  earlier  years  he 
had  needed  the  barber  once  only  in  two  or  three 
weeks,  he  now  visited  his  beard-trimmer  once  a 
week." 


THE  OEGANS  OF  REPBODUCTION         107 


Dr.  Steinach  has  recently  summarized  his  work 
in  an  article  for  a  technical  journal  entitled  Ver- 
jungung  durch  experimentelle  Neubelebung  der 
alternden  Pubertatsdruse;  which  may  be  translated' 
into  "Rejuvenation  through  experimental  revivify- 
ing of  the  senescent  puberty  (interstitial)  glands." 
This  article  under  the  short  title  of  Verjungung 
has  since  been  published  in  book  form  (by  Springer, 
of  Berlin). 

Professor  Steinach's  work  receives  support  from 
that  of  Dr.  Lichtenstern,  a  lecturer  at  the  Univer- 
sity of  Vienna,  who  has  successfully  performed  21 
transplantations  and  36  operations  in  cases  of 
senility.  Yet  we  must  also  observe  that  Professor 
Kolber,  another  colleague  of  Dr.  Steinach's,  who 
has  made  a  careful  histological  study  of  the  inter- 
stitial cells  with  the  view  to  elucidating  their  func- 
tion, is  not  wholly  in  agreement  with  Steinach ;  and 
perhaps  in  the  form  of  a  word  of  warning,  if  only 
to  ward  off  too  much  optimism,  it  may  well  be  asked 
why  the  repairment  of  a  part  of  the  organism — a 
very  important  part,  we  admit — that  has  become 
very  generally  dilapidated,  should  rejuvenate  the 
entire  bodily  machine.  It  must  be  remembered  that 
not  only  the  interstitial  gland,  but  the  other  duct- 
less glands,  are  affected  with  the  onset  of  old  age, — 
to  say  nothing  of  the  rest  of  the  organism. 

Voronoff. — Dr.  Serge  Voronoff  is  another  inves- 
tigator who  has  lately  appeared  before  newspaper 


108       GLANDS  IN  HEALTH  AND  DISEASE 

readers.  He  is  the  Director  of  Experimental 
Surgery  at  the  Laboratory  of  Physiology  of  the 
College  de  France,  a  position  once  held  by  perhaps 
the  greatest  of  all  physiologists,  Claude  Bernard. 

Unlike  Steinach,  Voronoff  decided  on  the  graft- 
ing procedure.  His  preliminary  experiments  on 
animals — on  sheep  and  goats — are  valuable  contri- 
butions to  the  literature  of  the  subject.  His  sub- 
sequent work  on  man  was  limited  to  two  recorded 
cases,  and  here  the  graft  does  not  refer  to  the  sexual 
glands  at  all,  but  to  the  thyroid.  We  are,  however, 
assured  that  but  for  the  scarcity  of  orang-utangs 
more  cases  could  have  been  presented,  and  the  effect 
of  the  transplantation  of  the  sex  gland  of  the  mon- 
key to  man  could  also  have  been  recorded.  But 
let  us  proceed  to  those  portions  of  VoronofFs  work 
that  are  of  value  to  us. 

Dr.  Voronoff  tells  us  that  he  has  made  some  120 
different  experiments  on  the  effects  of  testicular 
grafting  in  sheep  and  goats.  Grafts  were  at- 
tempted on  normal  males  and  females,  castrated 
males  and  females,  and  old  males  incapable  of  re- 
production. As  the  results  with  the  females  were 
in  no  instance  encouraging,  these  may  be  dismissed 
altogether,  and  our  attention  confined  to  the  males. 

Of  the  two  methods  of  grafting  which  are  em- 
ployed, and  which  have  already  been  described, 
Dr.  Voronoff  chose  the  simpler,  namely,  the  trans- 
plantation under  the  skin  or  in  the  peritoneum. 


THE  ORGANS  OF  REPRODUCTION"         109 

Later  on  he  found  that  the  very  best  results  were 
obtained  when  the  grafts  were  placed  in  the  vaginal 
tunics.  As  this  simple  method  of  grafting  gives 
better  results  when  fragments  rather  than  whole 
organs  are  used — in  other  words,  when  smaller 
rather  than  larger  pieces  are  used — Voronoff 
grafted  fragments  obtained  from  a  whole  testicle. 

In  one  set  of  experiments  three  he-goats  were 
castrated  and  testicular  grafts  introduced.  One  at 
the  end  of  four,  another  at  the  end  of  twelve,  and  a 
third  at  the  end  of  sixteen  months  all  showed 
"magnificent  horns  such  as  are  never  seen  on  cas- 
trated animals."  They  were  lively,  belligerent,  did 
not  grow  fat,  and  showed  much  sex  ardor. 

In  another  experiment  a  ram  12  to  14  years  old, — 
corresponding  to  about  80  years  in  man — which 
could  hardly  totter,  had  implanted  the  fragments 
of  a  testicle  obtained  from  a  young  ram.  "Two 
months  after  the  graft  had  been  effected  the  ani- 
mal was  completely  transformed.  His  urinal  in- 
continence had  disappeared;  so  had  tremblings  of 
the  legs ;  and  he  no  longer  looked  afraid.  His  bodily 
carriage  had  become  magnificent,  he  behaved  in  a 
lively  and  aggressive  manner.  The  old  ram  had 
taken  on  the  appearance  of  remarkable  youth  and 
vigor.  He  was  isolated  in  a  small  stable,  together 
with  a  young  ewe-lamb,  which  afforded  the  oppor- 
tunity for  observing  not  only  the  awakening  of  his 
sexual  instincts,  which  he  had  lost  years  ago,  but 


110      GLANDS  IN  HEALTH  AND  DISEASE 

also  the  following  more  tangible  result:  the  ewe- 
lamb  covered  by  him  in  September,  1918,  dropped  a 
vigorous  lamb  in  February,  1919.  There  is  nothing 
in  the  fact  to  cause  surprise.  Old  animals,  like 
very  aged  men,  occasionally  still  possess  spermato- 
zoids  which  are  altogether  alive,  but  it  is  the  atro- 
phy of  the  internal  secretive  glands  which  prevents 
their  experiencing  the  sexual  appetite  and  mani- 
festing their  virility." 

Dr.  Voronoff's  next  procedure  with  the  rejuve- 
nated animal  was  excellent  from  the  scientific 
standpoint.  He  removed  the  graft.  Three  months 
later  the  animal  had  completely  aged.  Then  he  re- 
implanted  another  graft  from  the  testicle  of  a 
younger  animal.  Once  again  the  animal  showed 
signs  of  rejuvenation.  Nothing  in  the  whole  book 
approaches  in  value  this  particular  experiment. 

At  the  time  of  writing  the  graft  had  been  in  its 
place  for  a  year  and  the  animal  was  still  in  excel- 
lent condition.  Even  if  we  could  reason  by  analogy, 
— which  in  this  instance  we  should  be  careful  not 
to  do — we  could  hardly  draw  any  far-reaching  con- 
clusions as  to  the  length  of  time  old  age  could  be 
warded  off  in  man. 

Having  successfully  performed  experiments  on 
animals,  Dr.  Voronoff  next  turned  his  attention  to 
man.  Here  a  difficulty  immediately  arose.  How 
was  he  to  get  a  healthy  young  man's  gland  in  order 
to  implant  it  into  an  old  man's  system?  If  only 


THE  ORGANS  OF  REPRODUCTION    111 

the  foolish  public  would  permit  him  to  preserve  the 
glands  of  all  healthy  young  men  that  are  acciden- 
tally killed !  But  the  foolish  public  will  do  nothing 
of  the  sort,  and  experience  has  shown  that  only 
glands  of  the  same  species  are  of  any  value.  There 
is  one  way  out  of  the  difficulty.  It  is  to  make  use 
of  the  higher  form  of  ape,  such  as  the  orang-utang 
or  chimpanzee,  whose  near  relationship  to  man  is 
to-day  firmly  established. 

Why  in  the  only  two  recorded  cases  of  grafts  of 
monkey  glands  on  human  beings,  men  suffering 
from  a  deficiency  of  the  thyroid  hormone  were  se- 
lected is  not  clear.  It  is  possible  that  no  aged  men 
willing  to  be  experimented  on  with  testicular  ex- 
tracts were  just  then  on  hand;  neither  is  it  easy  to 
obtain  monkeys  whenever  you  need  them. 

"There  is  no  question,"  writes  Dr.  Nagel,  "that 
Voronoff  had  a  great  idea  and  that  operations  ac- 
cording to  his  theory  were  temporarily  encourag- 
ing. They  do  not,  however,  last.  As  'soon  as  the 
gland  that  has  been  transplanted  has  been  absorbed 
by  the  body,  the  subject  of  the  experiment  returns 
to- his  original  condition. 

"In  Steinach's  operation  this  is  not  the  case. 
He  does  not  transplant.  He  merely  ties  off  the 
offending  gland,  the  inert  part  is  absorbed  by  the 
body,  and  a  new  one  is  grown  by  nature  in  place 
of  the  old,  useless  one. 

"What  does  a  gardener  do  when  he  wants  to  in- 


GLANDS  IN  HEALTH  AND  DISEASE 

vigorate  a  tree?  He  cuts  off  the  dead  and  dying 
branches  and  immediately  new  ones  are  thrown  out 
by  nature. 

"An  illustration  may  be  had  in  common  surgery. 
When  it  becomes  necessary  to  sever  an  artery  the 
surgeon  ties  it  off.  Very  shortly  the  checked  cir- 
culation would  cause  serious  trouble.  But  nature 
takes  care  of  that.-  The  moment  the  artery  is  tied 
off  little  shoots  spring  out  from  the  walls  of  both 
ends  of  the  main  artery,  growing  rapidly  until  they 
unite  around  the  useless  part  and  the  artery  is 
whole  again. 

"It  is  just  that  way  with  the  gland  tied  off  by 
Steinach.  A  new  one  grows,  and,  being  new,  is  far 
better  than  any  attempted  rejuvenation  of  the  old, 
dying  one." 

We  may  summarize  the  work  both  of  Professor 
Steinach  and  of  Dr.  Voronoff  by  saying  that  while 
experiments  on  animals  have  yielded  results  that 
are  of  great  value  and  that  are  extremely  sugges- 
tive, those  carried  out  on  human  beings  have  been 
altogether  too  few  to  warrant  any  hasty  generaliza- 
tions. We  are  far,  perhaps  very  far,  from  the  time 
when  the  mere  grafting  of  one  of  the  ductless 
glands  will  cause  old  age  with  all  its  concomitant 
horrors  to  disappear. 

Before  dismissing  this  subject  it  should  be  men- 
tioned that  Lorand,  a  Spanish  investigator,  is  of  the 
opinion  that  senility  is  the  result  of  primary  degen- 


THE  OKGANS  OF  REPKODUCTION    113 

eration  of  all  the  ductless  glands,  and  not  merely 
the  genital  glands.  In  one  of  his  latest  papers 
(June,  1921)  he  says  that  he  has  been  very  success- 
ful in  arresting  the  signs  of  senility  by  a  combina- 
tion of  thyroid  and  genital  gland  extract  treatment, 
especially  in  women.  But  let  not  the  enthusiasm  of 
a  few  individuals  make  us  too  credulous.  The  sub- 
ject has  pitfalls  at  every  step,  and  not  only  the  in- 
nocent layman,  but  many  a  physician  is  apt  to  slip. 
Pubertds  preco®. — So  far  our  discussion  has 
been  limited  to  cases  of  diminished  or  hypo-secre- 
tion of  the  interstitial  gland.  'We  have  seen  that 
such  cases  may  occur  naturally,  as  in  eunuchoids; 
and  we  are -probably  not  far  wrong  in  including  old 
men  and  perhaps  old  women  under  this  heading, 
though  their  condition  is  much  more  complex.  We 
have  already  seen  how  the  hypo  condition  can  be 
deliberately  brought 'about  by  means  of  castration. 
The  grafting  of  another  gland  from  a  more  vigor- 
ous animal  of  the  same  species,  or  the  adoption 
of  an  operative  technique  whereby  the  interstitial 
cells,  and  consequently  their  hormonic  output,  in- 
creases, brings  about  cures  that  may,  or  may  not 
be  permanent  (our  information  on  this  point  is 
nowhere  near  as  complete  as  it  might  'be) .  Now 
the  question  naturally  arises,  are  instances  of  ex- 
cessive or  hyper-secretion  met  with?  And  is  it  pos- 
sible to  induce  such  a  hyper-secretion  just  as,  let  us 
say,  it  is  possible  to  induce  a  hyper-thyroidism? 


GLANDS  IN  HEALTH  AND  DISEASE 

In  answering  the  second  question  first,  we  may 
point  ont  that  the  number  of  experiments  dealing 
with  induced  hyper-secretion  of  the  interstitial 
gland  is  limited.  Those  of  Brown-Sequard  on  the 
injection  of  testicular  extracts  have  already  been 
described,  and  we  know  that  his  experiments  left 
much  to  be  desired.  There  are,  however,  individ- 
uals that  have  been  known  to  suffer  from  an  ex- 
cessive secretion.  As  might  be  anticipated,  this 
occurs,  if  at  all,  at  a  very  early  age.  Such  cases 
go  under  the  name  of  pubertas  precox,  to  indicate 
early  sexual  maturity.  They  are  often  associated 
with  tumor  growths. 

One  of  the  most  interesting  examples  of  hyper- 
secretion  is  that  given  by  Sacchi.  A  boy  had  de- 
veloped quite  normally  until  he  was  five  and  a  half 
years  old.  From  that  time  on  until  he  was  nine 
and  a  half  the  .boy  changed  remarkably.  His  voice 
deepened,  hair  grew  on  his  face,  and  when  he  had 
reached  the  age  of  nine  and  a  half  years  he  actually 
had  a  black  beard.  An  examination  of  his  left  testi- 
cle revealed  a  tumor  growth.  This  was  removed. 
The  child  became  quite  normal  again. 

Another  .example  is  that  of  a  girl  of  seven,  who 
had  already -menstruated  a  number  of  times,  and 
who  had  well-developed  breasts  and  pubic  hair.  A 
tumor  of  the  ovary  was  removed,  and  the  girl  grew 
up  into  normal  womanhood. 


CHAPTER  VII 

THE  PANCREAS  AND  THE  LIVER 

Along  the  lower  part  of  the  stomach,  and  con- 
nected with  the  spleen,  is  a  gland  shaped  like  a 
dog's  tongue,  weighing  about  three  and  a  half 
ounces,  and  having  a  length  of  about  eight  inches. 
This  gland,  the  "pancreas" — from  the  Greek  "all 
flesh" — is  popularly  known  as  "sweetbread." 

The  pancreas. — The  pancreas  is  the  most  impor- 
tant organ  of  digestion.  Its  glands  secrete  sub- 
stances (enzymes)  which,  by  means  of  a  duct,  find 
their  way  into  the  small  intestine,  and  there  attack 
the  food  coming  from  the  stomach,  breaking  the 
food  particles  up  into  such  simple  chemical  sub- 
stances as  to  make  them  fit  for  absorption  by  the 
blood  and  lymph. 

It  was  not  known — definitely  at  least — until 
1889  that  this  organ  had  any  other  function  than 
that  of  taking  part  in  the  digestive  process.  Until 
then  the  pancreas  was  regarded  as  a  gland  produc- 
ing an  external  secretion  only — that  is,  a  secretion 
which,  once  manufactured,  is  sent  by  means  of  a 
tube  to  the  surface,  and,  in  this  particular  case, 

115 


116       GLANDS  IN  HEALTH  AND  DISEASE 

ultimately  finds  its  way  to  the  small  intestine.  In 
1889  Minkowski  and  von  Mering,  two  German  in- 
vestigators, proved  that  in  addition  to  its  external 
secretion,  it  also  produces  an  internal  one — a  se- 
cretion that  passes  directly  into  the  blood  stream, 
and  one  that  regulates  the  sugar  metabolism  of  the 
body.  Since  this  sugar  or  carbohydrate  metabo- 
lism is  one  that  is  inseparably  connected  with  an 
important  function  of  the  liver,  a  few  words  must 
be  said  regarding  that  organ. 

The  liver. — The  liver,  which  is  situated  on  the 
right  side  of  the  body  and  partly  covers  the  stom- 
ach, is  the  largest  gland  of  the  body.  It  weighs 
from  three  and  a  half  to  four  pounds.  It  produces 
an  external  secretion,  the  bile,  which  is  either  first 
stored  in  the  gall  bladder  until  wanted,  or  is  sent 
directly  into  the  small  intestine,  meeting  the  secre- 
tion from  the  pancreas,  and  helping  the  latter  in 
its  work  of  digestion.  But  it  does  far  more.  It  is 
the  seat  of  carbohydrate  metabolism  in  the  body. 

Carbohydrate*  metabolism. — Now  what  do  I  mean 
by  "carbohydrate  metabolism"?  Carbohydrates 
are  one  of  the  three  classes  of  foodstuffs,  and 
they  include  such  substances  as  sugar  and  starch 
(in  flour,  say) .  When  we  eat  one  or  more  of  these 
carbohydrates  they  may  or  may  not  be  broken  up  in 
the  digestive  tube  into  chemically  simpler  sub- 
stances. If  they  are  chemically  complex,  such  as 
starch,  they  will  be ;  If  they  are  chemically  simple, 


THE  PANCREAS  AND  THE  LIVER         117 

such  as  glucose,  they  will  not  be.  In  any  case, 
enzymes  secreted  by  the  •  sail  vary,  pancreatic  and 
intestinal  glands  and  sent  into  the  digestive  tract, 
are  ever  ready  to  convert  complex  into  simple 
carbohydrates.  The  chemically  simple  carbo- 
hydrates, of  which  there  are  three  well-known 
types  (glucose,  levulose,  galactose),  are  absorbed 
by  the  blood,  sent  to  the  liver  and  there  stored  in 
the  form  of  glycogen  or  "animal  starch." 

Glycogen. — Chemically,  glycogen  is  about  as 
complex  as  starch.  If,  therefore,  the  simple  carbo- 
hydrates, obtained  from  starch  and  similar  bodies 
by  the  breaking  up  of  the  starch  molecule,  are  con- 
verted in  the  liver  into  glycogen,  it  can  mean  but 
one  thing:  that  there  must  be  a  recombination  of 
the  simple  carbohydrate  molecules  to  form  gly- 
cogen. 

But  this  is  not  all.  Whenever  the  body  needs 
carbohydrate — which  it  does  much  of  the  time  for 
its  energy  supply — it  calls  on  this  glycogen  stored 
in  the  liver.  The  glycogen  is  first  converted  back 
again  into  a  simple  sugar — but  one  only — namely 
glucose,  and  this  glucose  is  sent  via  the  blood  to  the 
various  muscles,  where  it  is  "burnt"  to  supply  the 
fuel  needs  of  the  body. 

Summarizing  then  the  glycogen  function  of  the 
liver,  we  may  say  that  the  carbohydrates  we  eat, 
after  an  appropriate  preliminary  simplification  in 
the  digestive  tract,  are  transferred  to  the  liver  by 


118      GLANDS  IN  HEALTH  AND  DISEASE 

the  blood,  and  stored  there  in  the  form  of  glyco- 
gen.  Whenever  the  body  needs  carbohydrates  for 
its  various  energy  purposes,  the  glycogen  is  decom- 
posed into  glucose,  and  this  substance  is  sent  to  the 
various  tissues  where  it  is  "burnt"  or  "oxidized" 
into  carbon  dioxide  and  water. 

The  liver  a  ductless  gland. — You  will  remember 
that  we  defined  a  ductless  gland  as  one  producing 
a  secretion  which  passed  directly  into  the  blood, 
and  which  secretion  contained  a  something  (hor- 
mone) that  influenced  other  organs  to  various 
modes  of  activity.  Can  the  liver  be  viewed  as  a 
ductless  gland?  It  certainly  produces  an  internal 
secretion  in  the  sense  of  being  able  to  take  material 
(simple  carbohydrates)  from  the  blood,  converting 
it  into  other  products  (first  into  glycogen  and  then 
into  glucose),  and  passing  the  glucose  directly  into 
the  blood.  But  where  is  the  hormone,  -the  substance 
that  influences  the  activity  of  other  organs?  We 
must  look  to  the  pancreas  for  such  a  substance. 

Claude  Bernard. — At  any  rate,  the  glycogen 
function  of  the  liver  *  is  of  extraordinary  interest, 

*Not  only  does  the  liver  manufacture  glycogen,  but  it  also 
makes  urea  from  ammonia  and  carbon  dioxide.  This  urea  is 
carried  away  by  the  blood  and  finds  its  way  into  the  urine.  80 
per  cent,  of  the  total  nitrogenous  products  (representing  sub- 
stances derived  from  protein)  in  the  urine  is  in  the  form  of  urea. 
The  formation  of  urea,  like  that  of  glycogen,  is  evidence  of  the 
internal  secretory  mechanism  of  the  liver.  This  by  no  means 
exhausts  the  functions  of  the  liver,  a  veritable  storehouse  of 
wonders. 

It  should  be  remarked  at  this  point  that  a  rigid  definition  of 


THE  PANCREAS  AND  THE  LIVER         119 

since  its  discovery  and  study  led  the  celebrated 
French  physiologist,  Claude  Bernard,  to  formulate 
for  the  very  first  time  the  conception  of  an  internal 
secretory  gland.  In  his  justly  famous  Legons  de 
physiologic  experimentale,  published  as  far  back  as 
1855,  he  writes :  "For  a  time  a  false  conception  has 
been  current  as  to  what  a  secretory  organ  consists 
of.  It  was  believed  that  all  secretions  must  be 
poured  upon  an  internal  or  external  surface,  and 
that  all  secretory  organs  must  necessarily  be  pro- 
vided with  an  excretory  duct  for  the  purpose  of 
conveying  to  the  exterior  the  products  of  secretion. 
The  case  of  the  liver  establishes  in  a  most  lucid 
manner  that  there  are  internal  secretions,  that  is, 
secretions  which,  instead  of  being  carried  to  the 
exterior,  are  diffused  directly  into  the  blood.  .  .  . 
It  is'now  firmly  established  that  the  liver  has  two 
functions  of  the  nature  of  secretion.  The  first, 

an  internal  secretory  gland  would  rule  out  the  liver,  since  neither 
glucose  nor  glycogen,  the  substances  manufactured  by  it,  can  be 
regarded  as  hormones.  However,  it  has  historical  importance  in 
connection  with  Claude  Bernard's  work. 

If  we  want  to  stretch  our  definition,  we  could  well  afford  to 
include  such  a  substance  as  carbon  dioxide  in  a  list  of  hormones. 
It  is  the  amount «of  this  gas  in  the'blood,  and  not,  as  has  been 
supposed,  the  amount  of  oxygen,  that  controls  the  process  of 
breathing.  Increased  exertion,  as  in  running,  causes  increased 
production  of  carbon  dioxide,  .and  this  in  turn  stimulates  more 
rapid  breathing. 

A  very  practical  use  of  this  new  knowledge  has  been  made  by 
Yandel  Henderson,  the  Yale  physiologist.  It  is  only  a  too  well 
known  fact  that  after  anesthesia  the  patient's  breathing  is 
poor.  Professor  Henderson  shows -that  this  can  b«  improved  by 
adding  carton  dioxide  to  the  air  that  is  administered. 


120      GLANDS  IN  HEALTH  AND  DISEASE 

the  external  secretion,  produces  the  bile,  which 
flows  to  the  exterior ;  the  second,  the  internal  secre- 
tion, forms  sugar  which  immediately  enters  into 
the  blood  of  the  general  circulation." 

Claude  Bernard,  in  fact,  coined  the  phrase  "in- 
ternal secretion,"  though  his  views  as  to  the  influ- 
ence of  this  secretion  on  the  rest  of  the  body,  if 
not  vague,  were  misleading. 

The  pancreas  and  its  internal  secretion. — It  is 
now  time  to  turn  to  Minkowski  and  von  Mering's 
experiments  which  proved  that  the  pancreas  regu- 
lates the  sugar  metabolism  by  means  of  a  hormone 
which  it  develops.  These  investigators  found  that 
by  carefully  and  completely  extirpating  the  pan- 
creas in  a  dog,  the  animal  develops  diabetes.  Such 
an  operation  was  invariably  followed  by  the  death 
of  the  animal  within  a  few  weeks,  but  during  those 
weeks  it  suffered  severely  from  the  sugar  disease. 

Diabetes,  as  you  may  know,  is  the — unfortu- 
nately— all  too  common  disease  wherein  the  body 
cannot  use  or  "burn"  all  the  sugar  that  it  gets,  with 
the  result  that  we  find  it  present  in  excessive  quan- 
tity in  the  blood  (hyperglycemia),  and  sooner  or 
later  an  excessive  quantity  of  sugar  appears  in  the 
urine  (glycosuria).  Since  the  liver  is  the  central 
organ  for  sugar  metabolism,  we  must  look  for  a  dis- 
turbance in  the  liver  function.  The  German  in- 
vestigators showed  that  such  a  disturbance  occurs 
when  the  pancreas  is  cut  out  of  the  system. 


THE  PANCREAS  AND  THE  LIVER         121 


But  you  may  ask,  how  do  we  know  that  the  pan- 
creas develops  an  internal  secretion  the  hormone 
of  which  travels  through  the  blood  to  the  liver? 
Why  cannot  we  assume  that  whatever  influence  the 
pancreas  exerts  on  the  liver  is  due  to  its  external 
secretion — to  the  pancreatic  juice  which,  by  means 
of  a  duct,  is  poured  into  the  small  intestine?  We 
can  answer  these  questions  very  definitely.  It  has 
been  shown  that  incomplete  removal  of  the  pan- 
creas— as  little  as  one-fourth  to  one-fifth  of  the  to- 
tal need  be  left — prevents  diabetes,  even  though 
all  connections  with  the  small  intestine  have  been 
interrupted,  and  all  flow  of  pancreatic  juice  has 
stopped.  Or  again,  the  ducts  of  the  gland  may  be 
tied,  or,  what  amounts  to  the  same  thing,  filled  with 
paraffin,  and  no  glycosuria  results.  But  the  most 
convincing  proof  that  the  pancreas  develops  an  in- 
ternal secretion  is  this :  after  complete  extirpation 
of  the  gland,  and  after  the  onset  of  the  disease,  the 
symptoms  of  diabetes  disappear  upon  the  grafting 
of  a  piece  of  pancreas  under  the  skin  or  into  the 
abdominal  cavity.  Here  whatever  communication 
is  open  between  the  grafted  pancreas  and  the  other 
organs  of  the  body  is  by  means  of  the  blood  and 
the  blood  only. 

Kecent  experimentation  tends  to  show  that  the 
internal  secretion  of  the  pancreas  is  not  developed 
by  the  pancreatic  cells  themselves  but  by  peculiarly 
shaped  groups  of  cells,  scattered  throughout  the 


122      -GLANDS  IN  HEALTH  AND  DISEASE 

pancreas  and  known  collectively  as  the  "Islands  of 
Langerhans,"  after  their  discoverer.  Ssobelow,  a 
Russian,  tied  the  pancreatic  duct  and  noticed  that 
the  pancreatic  cells  decayed;  but  not  so  the  cells 
of  the  "Islands  of  Langerhans."  We  have  already 
noticed  that  such  an  operation  is  not  followed  by 
the  appearance  of  sugar  in  the  urine,  whereas  sugar 
does  appear  upon  the  complete  extirpation  of  the 
pancreas.  Hence  it  seems  logical  to  conclude  that 
the  pancreatic  hormone  is  produced  by  the  "Is- 
lands" rather  than  by  the  pancreatic  cells  proper. 
This  view  finds  corroboration  in  the  observations 
of  clinicians  who  have  noticed  that  in  cases  of  dia- 
betes the  "Islands  of  Langerhans"  show  degenera- 
tion. 

How  the  amount  of  sugar  in  the  blood  is  regvr 
lated. — Just  how  the  pancreatic  hormone  regulates 
the  sugar  output  is  problematical.  Some  claim 
that  it  takes  a  hand  in  the  oxidation  of  glucose  to 
carbon  dioxide  and  water;  and  that  in  its  absence 
the  glucose  cannot  be  so  oxidized,  whence  it  ac- 
cumulates in  the  blood  and  finds  its  way  into  the 
urine.  Others,  on  the  contrary,  are  of  the  opinion 
that  it  has  nothing  at  all  to  do  with  the  oxidation 
of  glucose,  but  that  it  does  regulate  the  amount  of 
glucose  to  be  formed  from  the  glycogen  in  the  liver. 
In  the  absence  of  the  pancreatic  hormone,  the  regu- 
latory influence  being  absent,  excessive  quantities 
of  glycogen  are  converted  into  glucose,  which  finds 


THE  PANCREAS  AND  THE  LIVER         123 


its  way  into  the  blood  and  then  into  the  urine.  An 
attractive  hypothesis  of  this  type  claims  that  there 
really  are  two  opposing  forces  that  work  in  the 
normal  man, — an  accelerating  force,  due  to  the  hor- 
mone from  the  adrenal  glands,  which  accelerates 
the  conversion  of  glycogen  into  glucose,  and  a  re- 
tarding force,  due  to  the  pancreatic  hormone,  which 
tends  to  slow  up  and  regulate  such  a  reaction.  To 
support  this  hypothesis,  Dr.  Zuelzer,  its  author,  de- 
scribes an  experiment  with  a  dog  that  had  had  its 
pancreas  removed  and  its  adrenal  veins  ligated. 
No  diabetes  followed. 

We  may  represent  what  happens  as  follows: 

carbohydrates >  stored  in  liver  as  glycogen > 

given  out  as  glucose.  The  blood,  when  analyzed  is 
always  found  to  contain  a  small  amount  of  glucose. 
Under  normal  conditions  that  glucose  is  fairly  con- 
stant in  amount,  ranging  from  0.07  to  0.1  per  cent. 
Even  in  a  starving  animal  the  blood  sugar  is  found 
to  remain  constant.  This  makes  us  believe  that 
under  such  conditions,  with  all  carbohydrate  vir- 
tually absent  from  the  body,  part  of  the  fat  mole- 
cule, and  perhaps  part  of  the  protein  molecule,  is 
converted  into  sugar.  Only  in  pathological  cases, 
such  as  are  met  with  in  diabetes,  does  the  amount 
of  blood  sugar  materially  increase. 

Now  the  question  arises,  by  what  mechanism  is 
the  blood  sugar  of  the  normal  human  being  kept 
constant?  Why  despite  the  varying  quantity  of 


124       GLANDS  IN  HEALTH  AND  DISEASE 

carbohydrate  eaten  from  day  to  day  does  not  the 
blood  sugar  fluctuate  correspondingly?  A  num- 
ber of  hypotheses  have  been  advanced  to  explain 
this  controlling  mechanism.  Very  recently  (April, 
1921)  Dr.  Langfeldt  has  proposed  a  theory  which 
includes  the  best  elements  of  the  theories  of  other 
investigators  as  well  as  a  little  of  his  own  specu- 
lation. In  essence  it  is  this:  It  is  evident  that 
there  must  be  at  least  two  controlling  factors,  one 
involving  the  conversion  of  carbohydrates  into  gly- 
cogen,  and  the  other  the  conversion  of  glycogen 
into  glucose.  The  first  part  of  the  reaction,  the 
glycogen  synthesis,  is  controlled  by  the  pancreatic 
hormone;  the  second,  the  breaking  down  of  glyco- 
gen to  glucose,  with  the  object  of  meeting  the  en- 
ergy requirements  of  the  muscles,  is  a  more  com- 
plex affair  depending  for  one  thing  upon  the  degree 
of  acidity  of  the  blood.  It  has  been  shown  that  the 
glycogenase,  the  enzyme  responsible  for  the  trans- 
formation of  glycogen  to  dextrose,  is  most  active 
when  the  blood  is  slightly  acid.  Ingenious  physical 
chemists  have  devised  quantitative  methods  for  de- 
termining the  exact  state  of  acidity  not  only  of 
blood  but  of  any  liquid.  If  then  the  acidity  of  the 
blood  is  below  or  above  a  certain  optimum,  the  gly- 
cogenase is  not  so  active,  and  less  glucose  is  formed 
— a  rare  and  abnormal  condition. 

On  the  other  hand,  a  more  common  occurrence 
is  where  the  pancreatic  hormone  fails  to  function, 


THE  PANCREAS  AND  THE  LIVER         125 

due  to  the  failure  to  function  of  the  pancreas;  in 
that  case  little  of  the  carbohydrates  is  converted 
to  glycogen,  and  the  excess  sugar  floods  the  blood 
and  the  urine.  We  here  have  a  typical  case  of  dia- 
betes. 

The  "Allen  treatment"  for  diabetes. — No  men- 
tion of  diabetes  is  possible  without  referring  to  the 
Allen  treatment  of  this  disease.  Dr.  Allen,  until 
recently  with  the  Kockefeller  Institute,  and  now 
head  of  the  Physiatric  Institute,  Morristown,  N.  J., 
has  had  such  remarkably  good  results  with  his 
"fasting  treatments/'  that  physicians  all  over  the 
world  have  adopted  his  method,  and  there  can  be 
little  room  for  doubt  as  to  its  success.  Only  re- 
cently (June,  1921)  at  the  Wiesbaden  Congress  of 
Internal  Medicine,  the  two  foremost  authorities  on 
diabetes  in  Europe,  von  Noorden  and  Minkowski, 
sang  its  praises. 

The  treatment  is  as  follows:1  A  preliminary 
fast  is  taken  until  the  urine  is  free  from  sugar. 
This  will  usually  take  less  than  four  days.  During 
that  time  water  is  allowed  and  also,  to  a  certain 
extent,  tea  and  coffee.  Following  the  fast,  carbo- 
hydrate food  is  gradually  added,  at  first  in  the  form 
of  green  vegetables.  Coincident  with  the  addition 
of  carbohydrate,  or  in  place  of  it  if  the  carbohy- 
drate tolerance  is  very  low,  protein  is  added  to  the 

*This  is  described  in  the  Handbook  of  Therapy,  published  by 
the  American  Medical  Association. 


126       GLANDS  IN  HEALTH  AND  DISEASE 

diet  in  small  but  gradually  increasing  amounts  un- 
til glycosuria  occurs.  Fats  are  added  in  small 
amounts  during  the  time  of  addition  of  carbohy- 
drates and  proteins.  Frequent  urine  examinations 
are  made,  either  by  the  medical  attendant  or  by  the 
patient  himself1  and  the  diet  regulated  accord- 
ingly. 

1Some  Fehling's-Benedict  solution,  which  is  blue  in  color,  is 
heated  in  a  test  tube  until  it  boils,  and  an  equal  volume  of  the 
urine  under  examination  is  added.  The  mixture  is  heated  for  a 
minute  or  two.  If  sugar  is  present,  a  red  precipitate  will  make 
its  appearance,  and  the  amount  of  precipitate  will  give  some 
rough  idea  of  the  amount  of  sugar  present.  A  modification  of 
this  method  lends  itself  to  a  fairly  exact  quantitative  estimation. 

The  more  recent  work  on  the  subject  has  centered  itself  as  much 
in  determining  the  quantity  of  sugar  in  the  blood  as  in  that  of 
the  urine,  and  much  ingenuity  has  been  expended  to  devise 
methods  that  are  refined  enough  when  dealing  with  quantities  of 
blood  even  as  small  as  a  drop  or  two — the  amount  obtained  from 
a  prick  in  a  finger.  The  blood  being  not  only  the  medium  by 
which  materials  are  taken  in  by  the  body,  but  also  that  by  which 
they  are  given  out,  it  need  cause  little  surprise  that  blood 
analyses  should  throw  much  light  on  what  takes  place  in  the 
body. 


CHAPTER  VIII 

THE  INTESTINAL  HORMONE 

We  have  already  referred  (page  4)  to  the  work 
of  the  English  physiologists,  Bayliss  and  Starling, 
on  secretin.  This  work  is  of  such  a  fundamental 
character,  that  it  well  deserves  a  chapter  all  to 
itself. 

In  the  preceding  chapter  we  have  shown  how 
the  glycogenic  function  is  controlled  by  a  hormone 
developed  by  the  pancreas.  We  shall  now  proceed 
to  show  that  the  pancreatic  juice  in  turn  is  con- 
trolled by  a  hormone  which  has  its  origin  in  the 
lining  of  the  upper  part  of  the  small  intestine. 

Digestion  in  the  small  intestine. — Even  at  the 
risk  of  repeating  what  was  said  in  the  introduction, 
let  us  state  what  happens  in  the  small  intestine 
during  digestion.  You  will  remember  that  when 
the  valve  connecting  the  stomach  and  intestine  is 
opened,  the  food  passes  from  the  former  into  the 
latter.  Here  the  food  is  acted  upon  by  three  liq- 
uids, each  containing  either  enzymes  or  other  sub- 
stances that  help  to  simplify  the  food  to  the  point 
where  it  can  be  absorbed  by  the  blood  and  lymph 

127 


128       GLANDS  IN  HEALTH  AND  DISEASE 

and  sent  to  the  cells.  One  of  these  liquids  is  elab- 
orated by  the  intestine  itself;  another,  the  bile, 
comes  from  the  liver ;  and  the  third,  the  pancreatic 
juice,  from  the  pancreas. 

The  last  two  reach  the  intestine  by  means  of 
ducts  or  tubes.  They  represent  typical  "external 
secretions,"  in  contradistinction  to  the  "internal 
secretions"  that  we  have  studied,  and  that  flow  di- 
rectly into  the  blood. 

The  hormone  in  the  intestine. — Now  the  ques- 
tion arises,  why  whenever  food  enters  the  intestine, 
and  only  then,  do  bile  and  pancreatic  juice  also 
begin  to  flow  into  it?  The  easiest  answer,  the  most 
obvious  one,  is  that  there  is  a  nervous  mechanism 
involved ;  that  the  brain  correlates  the  activities  of 
these  organs.  Such  a  theory  had  a  distinguished 
supporter  in  the  person  of  Pavlov,  the  Kussian 
physiologist,  whose  present  plight  has  been  so 
graphically  described  by  H.  G.  Wells,  the  novelist 
who  is  also  a  scientist.  We  are  about  to  show  that 
Pavlov's  theory  of  brain  interference  is  untenable ; 
that  all  nerve  connections  between  the  brain  and 
intestine  can  be  severed  without  stopping  the  flow 
of  pancreatic  juice;  that  the  chief  factor  that  brings 
about  this  coordination — at  least  in  so  far  as  the 
flow  of  pancreatic  juice  is  concerned,  and,  to  a  less 
extent,  the  bile, — is  a  hormone  elaborated  by  the 
small  intestine;  that  this  hormone  is  produced 
whenever  the  acid  food  from  the  stomach  finds  its 


THE  INTESTINAL  HOKMONE  129 

way  into  the  intestine;  and  that  this  hormone,  once 
produced,  finds  its  way  to  the  pancreas  via  the 
blood  stream.  You  will  notice  incidentally  that 
if  what  we  now  say  is  true,  the  intestine  is  similar 
to  the  pancreas  and,  according  to  Claude  Bernard, 
to  the  liver,  in  that  it  elaborates  both  an  internal 
and  an  external  secretion. 

The  proof  that  the  flow  of  pancreatic  juice  is  con- 
trolled by  a  hormone  elaborated  by  the  intestine 
is  due  to  Bayliss  and  Starling,  the  presiding  gen- 
iuses of  the  department  of  physiology  at  Univer- 
sity College,  London.  Their  experiment  marks  a 
milestone  in  the  development  of  our  knowledge  of 
internal  secretions;  and  we  shall  offer  no  excuse 
for  quoting  from  part  of  their  celebrated  paper  on 
the  subject,  technical  though  it  is. 

Bayliss  and  Starling's  experiment. — "On  Janu- 
ary 16, 1902,  a  bitch  of  about  6  kilos  (13-14  pounds) 
weight  which  had  been  fed  about  18  hours  previ- 
ously, was  given  a  hypodermic  injection  of  morphia 
some  three  hours  before  the  experiment.  The  ner- 
vous masses  and  celiac  (pertaining  to  the  abdomen) 
axis  were  completely  removed,  and  both  vagi 
(nerves  situated  in  this  part  of  the  body)  cut.  A 
loop  of  jejenum  (a  portion  of  the  small  intestine) 
was  tied  at  both  ends,  and  the  nerves  supplying  it 
were  carefully  dissected  out  and  divided,  so  that 
the  piece  of  intestine  was  connected  to  the  body  of 
the  animal  merely  by  its  arteries  and  veins.  A 


130      GLANDS  IF  HEALTH  AND  DISEASE 

cannula  (tube  for  inserting  into  body)  was  inserted 
in  the  large  pancreatic  duct  and  the  drops  of  se- 
cretion recorded.  The  blood  pressure  in  the  caro- 
tid (the  principal  artery  in  the  neck)  was  also 
recorded.  The  animal  was  in  a  warm  saline  bath, 
and  under  artificial  respiration. 

"The  introduction  of  about  20  cubic  centimeters 
(about  1-25  of  a  pint)  or  about  one  tablespoon  of 
four-tenths  per  cent,  of  hydrochloric  acid  x  into  the 
duodenum  (the  first  portion  of  the  small  intestine) 
produced  a  well-marked  secretion  of  one  drop  every 
20  seconds,  lasting  for  some  six  minutes;  this  re- 
sult merely  confirms  previous  work.  But — and 
this  is  the  important  part  of  the  experiment,  and 
the  turning  point  of  the  whole  research — the  in- 
troduction of  10  cubic  centimeters  of  the  same  acid 
into  the  enervated  loop  of  jejenum  produced  a 
similar  and  equally  marked  effect. 

"Now,  since  this  part  of  the  intestine  was  com- 
pletely cut  off  from  nervous  connection  with  the 
pancreas,  the  conclusion  was  inevitable  that  the 
effect  was  produced  by  some  chemical  substance 
finding  its  way  into  the  loop  of  jejenum  in  question, 
and  being  carried  in  the  blood  stream  to  the  pan- 
creatic cells.  Wertheimer  and  Le  Page  have  shown, 

1  Hydrochloric  acid  is  found  in  the  stomach  under  normal  con- 
ditions. It  is  approximately  four-tenths  of  one  per  cent,  in 
strength.  Of  course  the  object  in  introducing  the  acid  is  to 
prove  that  it,  and  it  alone,  coming  from  the  stomach,  liberates 
the  hormone  in  the  intestine. 


THE  INTESTINAL  HORMONE  131 

however,  that  acid  alone  introduced  into  the  circu- 
lation has  no  effect  on  the  pancreatic  secretion,  so 
that  the  body  of  which  we  were  in  search  could  not 
be  the  acid  itself." 

This  suggested  that  there  may  be  a  something  in 
the  wall  of  the  intestine  which  was  responsible  for 
the  action.  "The  next  step  in  our  experiment  was 
plain — namely,  to  cut  out  the  loop  of  jejenum, 
scrape  off  the  mucous  membrane  (tissue  covering 
the  surface),  rub  it  up  with  sand  and  four-tenths 
per  cent,  hydrochloric  acid  in  a  mortar,  filter 
through  cotton  wool  to  get  rid  of  lumps  and  sand, 
and  inject  the  extract  into  a  vein;  .  .  .  After  a 
period  of  about  20  seconds,  we  obtained  a  flow  of 
pancreatic  juice  at  more  than  twice  the  rate  pro- 
duced at  the  beginning  of  the  experiment  by  intro- 
duction of  acid  into  the  duodenum." 

A  pretty  variation  of  this  experiment  was  per- 
formed by  Enriquez  and  Hallion.  They  conveyed 
the  blood  stream  from  the  vessels  of  one  dog  (A) 
into  those  of  another  (B)  and  found  that  after  in- 
jecting acid  into  the  small  intestine  of  dog  (A), 
pancreatic  juice  began  to  flow  in  dog  (B)  ! 

Secretin. — Though  the  hormone  responsible  for 
the  flow  of  pancreatic  juice  has  not  been  isolated  in 
the  pure  state,  its  discoverers  have  given  it  the 
name  "secretin"  (from  the  Greek  "to  excite.") 
Since  a  watery  extract  of  the  mucous  membrane  of 
the  intestine  when  injected  into  the  blood  stream, 


132       GLANDS  IN  HEALTH  AND  DISEASE 

fails  to  cause  a  flow  of  pancreatic  juice,  and  since 
hydrochloric  acid  alone  is  no  better,  but  since  when 
the  two  are  mixed  we  do  get  a  response,  Professors 
Bayliss  and  Starling  have  advanced  the  hypothesis 
that  in  its  original  form  the  secretin  is  in  an  in- 
active state — the  "pro-secretin"  state  they  term  it; 
and  that  the  hormone  becomes  active  only  when 
the  acid  converts  the  pro-secretin  into  secretin. 
The  function  of  the  acid  coming  from  the  stomach, 
then,  is  to  convert  the  inactive  into  an  active  hor- 
mone. The  fact  that  solutions  containing  secretin 
can  be  boiled  without  destroying  the  hormone  sug- 
gests that  this  hormone — and  others? — are  quite 
distinct  from  either  vitamines  or  enzymes,  both  of 
which  are  quite  susceptible  to  increases  in  tempera- 
ture. 

An  objection  to  the  work  of  Bayliss  and  Starling. 
— The  Italian  physiologist,  Luciani,  has  criticized 
the  work  of  the  English  scientists.  He  writes : 1 
"Popielski  and  his  pupils  have  recently  published 
a  series  of  experiments  and  conclusions  which  com- 
pletely refute  the  secretin  theory.  Popielski  states 
that  the  substance  extracted  after  the  extraction 
of  the  duodenal  mucosa  with  hydrochloric  acid  is 
not  specific,  but  may,  on  the  contrary,  be  obtained 
by  simple  hydrolysis,  from  any  glandular,  muscu- 
lar, or  even  nervous  tissue.  .  .  .  But  the  follow- 
ing is  the  most  cogent  of  PopielskPs  arguments. 

1  Human  Physiology,  Volume  2. 


THE  INTESTINAL  HORMONE  133 

In  repeating  the  injections  of  sec  re  tin  many  times 
equal  doses,  he  observed  a  conspicuous  secretion 
tfter  the  first  dose,  less  after  the  second,  still  less 
!ter  the  third,  till  the  substance  rapidly  became 
[effective.  Now,  the  introduction  of  acid  in  the 
luodenum,  however  often  repeated,  invariably  ex- 
ites  pancreatic  secretion  proportional  to  the  quan- 
Ity  of  acid  introduced.  The  body  evidently  reacts 
the  introduction  of  secretin  by  forming  an  anti- 
>ody  capable  of  fixing  it  and  annulling  its  action ; 
tis  suggests  that  it  is  not  a  substance  normally 
Leveloped  by  the  body,  but  is  an  artificial  extrane- 
ms  product." 

Despite  this  criticism,  the  secretin  theory  has 
m  very  generally  adopted ;  to  every  physiologist 
cites  an  experience  in  opposition  to  it,  there 
ire  twenty  who  cite  experiments  that  support  it. 

Gastric  secretin. — While  on  the  subject  of  diges- 
tive juices,  reference  may  be  made  to  the  gastric 
juice,  a  fluid  manufactured  in  the  walls  of  the  stom- 
ach. Pavlov  has  conclusively  shown  that  the  flow 
of  gastric  juice  is  unquestionably  controlled  by  the 
brain,  since  the  severance  of  all  nerve  connections 
stops  the  flow.  This  would  seem  to  show  that  the 
origin  of  the  flow  of  gastric  and  pancreatic  juices 
is  fundamentally  different.  However,  Dr.  Edkins 
has  been  able  to  show  that,  in  addition  to  a  nervous 
reflex,  there  is  also  a  chemical  stimulus  involved. 
His  experiment  followed  the  lines  of  Bayliss  and 


134      GLANDS  IN  HEALTH  AND  DISEASE 

Starling.  A  piece  of  mucous  membrane  from  the 
stomach,  when  extracted  with  acid,  and  the  acid 
injected  into  the  blood,  caused  a  flow  of  gastric 
juice.  Edkins  called  the  hormone  responsible  for 
this  action  the  gastric  secretin,  to  distinguish  it 
from  the  intestinal  secretion. 

Secretin  and  vitamine. — We  have  pointed  out  in 
this  chapter  that  secretin  withstands  the  tempera- 
ture of  boiling  water,  a  fact  speaking  against  its 
identity  with  any  vitamine.  However,  Dr.  Carl 
Voegtlin,  the  government  chemist  in  the  Hygienic 
Department  at  Washington,  has  recently  performed 
experiments  to  show  that  secretin  and  vitamine  B 
(the  anti-neuritic  vitamine — that  is,  the  one  that 
cures  beriberi  in  man  and  polyneuritis  in  pigeons),1 
are  similar  in  properties,  if  not  actually  one  and  the 
same  substance.  Towards  chemical  reagents,  such 
as  wood  alcohol,  silver,  lead  and  barium  salts,  they 
behave  alike.  "Secretin  preparations  from  the  du- 
odenum of  hogs  relieved  to  some  extent  the  neuritic 
symptoms,  and  the  anti-neuritic  vitamine  from 
brewer's  yeast  on  injection  into  dogs  stimulated  the 
pancreatic  and  biliary  secretions."  Whether  this 
be  so  or  not  we  cannot  say  definitely;  the  work 
needs  confirmation. 

1  See  the  chapter  on  Beriheri  in  the  author's  book  on  Vitamines. 


CHAPTER  IX 

THYMUS,   SPLEEN,   PINEAL,   MAMMARY  GLAND  AND 
KIDNEY 

I  have  grouped  in  this  chapter  a  number  of  or- 
ins  whose  exact  position  in  ductless  glandular 
classification  is  debatable.    Some  of  the  organs  are 
tot   glandular  in   the  histological   sense.     With 
>thers  we  are  not  altogether  certain  that  they  pro- 
Luce  an  internal  secretion  or,  more  correctly,  a 
specific  hormone.    A  substance  like  carbon  dioxide 
is  not  produced  by  a  gland,  yet  as  a  regulator  of 
respiratory  activity  and  of  the  respiratory  center  it 
ought,  perhaps,  to  be  discussed  in  this  chapter.    On 
the  other  hand,  a  compound  like  urea  is  the  prod- 
uct of  an  organ  of  internal  secretion ;  but  it  is  not 
yet  certain  whether  it  has  any  direct  influence  on 
the  kidney.     This  chapter,  then,  is  full  of  uncer- 
tainties. 

THYMUS 

This  organ  is  situated  in  the  neck  near  the  thy- 
roid. It  seems  to  be  of  particular  importance  in 
the  early  life  of  the  individual,  though  the  most 

135 


136       GLANDS  IN  HEALTH  AND  DISEASE 

recent  work  tends  to  the  opinion  that  it  functions 
throughout  life.  After  the  second  year  of  life  it 
grows  less  in  size.  Here  are  some  figures :  At 
birth,  13.26  grams  (approximately  30  grams  equal 
one  ounce) ;  between  one  and  five,  33  grams;  be- 
tween six  and  ten,  26  grams ;  11  to  15,  37 ;  16  to  20, 
25;  56  to  65,  16;  66  to  75,  6. 

Function  of  the  thymus. — What  the  function  of 
the  thymus  is  is  a  matter  of  constant  debate.  A 
number  of  experiments  point  to  the  fact  that  its 
activity  is  connected  with  that  of  the  sex  glands; 
that  the  thymus,  for  a  time,  checks  the  development 
of  the  reproductive  organs.  For  example,  the  re- 
moval of  the  thymus  (in  animals)  is  said  to  ac- 
celerate sexual  development,  though  it  delays 
growth;  and  castrated  animals  show  an  enlarged 
thymus. 

Uhlenhuth,  of  the  Eockef  eller  Institute,  has  spon- 
sored the  theory  that  the  thymus  secretes  a  tetany- 
producing  substance  (see  the  chapter  on  the  para- 
thyroid) which  is  neutralized  by  the  parathyroids. 
Some  claim  that  the  thymus  is  the  principal  reserve 
organ  for  nucleoprotein,  an  important  type  of  pro- 
tein particularly  abundant  in  the  nuclei  of  cells. 
Still  others  deny  that  the  thymus  is  an  endocrine 
gland.  For  example,  Hopkins,  in  an  exhaustive  re- 
view of  the  subject,  says:  "The  evidence  in  favor 
of  such  a  theory  (that  the  thymus  is  a  ductless 


THYMUS  137 

gland)  is  circumstantial  at  best  and  very  meager. 
It  is  equally  difficult  to  prove  that  the  thymus  does 
not  produce  a  secretion,  but  the  burden  of  proof 
is  upon  those  who  support  the  former  theory." 

A  very  remarkable  experiment  by  Gudernatsch 
must  be  cited  here,  though  it  should  be  noted  at  the 
outset  that  another  investigator,  Swingle,  chal- 
lenges Gudernatsch's  statements.  The  latter  found 
that  by  feeding  tadpoles  with  thymus  extract,  their 
growth  could  be  accelerated  to  a  remarkable  de- 
gree, but  that  metamorphosis  to  the  frog  state  was 
delayed.  We  have  already  seen  in  the  chapter  on 
the  thyroid  that  thyroid  extract  behaves  in  an  op- 
posite manner,  in  that  feeding  tadpoles  with  such 
an  extract  accelerates  the  transformation  into  the 
frog,  but  retards  growth.  Are  we  to  assume  that 
the  thymus  is  connected,  for  a  time  at  least,  with 
thyroid  activity? 

The  general  concensus  of  opinion  is  that  the  ex- 
tirpation of  the  thymus  does  not  necessarily  result 
fatally,  though  it  does  give  rise  to  a  disordered  de- 
velopment of  the  skeleton,  such  as  may  be  seen  in 
a  rickety  child.  Sciplades,  a  Hungarian  investi- 
gator, is  of  the  opinion  that  osteomalacia,  a  disease 
characterized  by  a  softening  of  the  bones,  is  brought 
about  by  the  absence  of  a  functioning  thymus.  This 
is  based  on  experiments  with  young  dogs  whose 
thymus  had  been  completely  extirpated.  "The 


138       GLANDS  IN  HEALTH  AND  DISEASE 

changes  produced  in  the  bones  coincided,  histologi- 
cally,  with  the  changes  characteristic  of  human 
osteomalacia." 

Thymus  extract  does  not  cure  the  disease,  though 
when  injected  into  the  blood  it  lowers  the  arterial 
pressure  and  accelerates  the  heart  beat. 

A  disease  called  "mors  thymica,"  sometimes  "thy- 
mic  asthma,"  connected  with  difficult  breathing  of 
infants,  and  which  has  a  sudden  fatal  termination 
("thymus-death,")  is  said  to  be  due  to  the  hyper- 
trophy (enlargement  of  organ)  of  the  thymus. 

SPLEEN 

The  spleen,  like  the  thymus,  is  not  a  glandular 
organ,  and  hence  is  often  omitted  in  the  treatment 
of  ductless  glands.  But  it  seems  to  develop  an  in- 
ternal secretion,  in  that  a  hormone  from  the  spleen 
passes  through  the  blood  to  the  pancreas  and  "acti- 
vates" the  ferment  (enzyme)  that  attacks  protein — 
trypsin.  This  proof,  if  not  convincing,  is  of  a 
somewhat  more  positive  nature  than  in  the  case  of 
the  thymus,  where  our  only  reason  for  supposing 
that  it  manufactures  a  hormone  is  the  claim  made 
by  some  that  when  the  thymus  is  extirpated  the 
skeleton  does  not  develop  properly. 

The  function  of  the  spleen,  like  that  of  the  thy- 
mus, is  shrouded  in  much  mystery.  We  have  just 
said  that  it  is  possible  that  its  hormone  activates 


THYMUS  139 

the  pancreatic  trypsin.  It  should,  however,  be 
added  that  Pavlov,  the  Kussian  physiologist,  has 
proved  that  the  juice  elaborated  in  the  small  in- 
testine also  contains  a  hormone  (or  enzyme?) 
which  activates  the  trypsin. 

From  the  large  quantity  of  iron  (in  "organic" 
combination)  that  the  spleen  contains,  and  from 
studies  in  anemia,  investigators  have  concluded 
that  it  plays  a  part  both  in  the  formation  and  de- 
struction of  the  red  blood  corpuscles,  but  this  is  by 
no  means  certain.  Others  regard  it  as  playing  an 
important  part  in  immunity  from  the  active  pha- 
gocytosis (destruction  of  micro-organisms  by  cells 
such  as  the  leucocytes,  or  white  corpuscles  of  the 
blood).  The 'very  recent  work  by  Inlow  disproves 
the  theory  that  the  spleen  regulates  the  digestive 
power  of  the  stomach — a  claim  based  on  some  ex- 
periments which  are  cited  to  prove  that  the  re- 
moval of  the  spleen  diminishes  the  activity  of  the 
pepsin,  the  enzyme  in  the  stomach. 

Curiously  enough,  the  extirpation  of  the  organ 
was  practised  by  the  ancients,  in  the  belief  that  it 
improves  the  "wind"  in  runners.  Extirpation  is 
not  attended  with  fatal,  or  even  particularly  bad 
results.  It  is  practised  in  a  disease  called  "splenic 
anemia,"  "characterized  by  progressive  enlarge- 
ment of  the  spleen,  attacks  of  anemia,  and  a  tend- 
ency to  hemorrhages.  .  .  ."  Complete  recovery 
follows  the  removal  of  this  organ.  This,  of 


140       GLANDS  IN  HEALTH  AND  DISEASE 

course,  makes  it  quite  evident  that  the  spleen  can- 
not compare  in  importance  with  other  ductless 
glands,  such  as  the  adrenal  or  the  pancreas,  the 
absence  of  which  causes  death.  This,  however,  does 
not  mean  that  the  spleen  is  of  no  importance. 

Eddy  in  a  recent  review  cites  the  following  in 
support  of  the  theory  that  the  spleen  produces  an 
internal  secretion:  1.  Changes  in  erythrocytes 
after  splenectomy  (removal  of  spleen) ;  2.  Modifi- 
cation of  blood  picture  after  hyperplasia  (abnor- 
mal multiplication  of  the  tissue  elements)  of  the 
spleen,  ameliorated  in  some  cases  at  least  by  splen- 
ectomy ;  3.  Specific  effects  on  the  red  blood  corpus- 
cles of  injection  of  splenic  extract.  He  acknowl- 
edges that  we  know  nothing  of  the  chemical  na- 
ture of  the  hormone,  but  suggests  that  the  chief 
function  of  the  spleen  is  to  remove  from  the  circu- 
lation the  disintegrated  erythrocytes  (red  blood 
cells),  and  to  build  erythrocytes  (by  stimulating 
the  erythrogenic,  or  blood  corpuscle  building  power 
of  the  bone  marrow) . 

PINEAL  ("Epiphysis") 

This  is  an  organ  the  size  of  a  pea,  situated  at  the 
base  of  the  brain,  behind  and  above  the  pituitary. 
Descartes  considered  it  the  seat  of  the  soul !  Like 
the  thymus,  its  importance  seems  to  be  chiefly  in 
the  early  stages  of  its  existence — if  we  are  to  be- 
lieve many  of  the  authors  who  have  busied  them- 


PINEAL  141 

selves  with  the  organ.  Professor  Biedl  claims  that 
in  adults  "the  gland  is  a  negligible  factor/'  He  ar- 
rives at  this  conclusion  from  extirpation  experi- 
ments. He  has  not,  however,  settled  the  question 
of  extirpation  in  young  animals. 

Foa,  an  Italian,  has  removed  the  pineal  from 
roosters,  with  the  result  that  the  testes  hypertro- 
phied.  Horrax,  of  Chicago,  has  practised  pineal- 
ectomy  on  guinea  pigs;  he  states  that  the  develop- 
ment of  the  testes  becomes  accelerated.  The  feed- 
ing of  the  desiccated  pineal  body  to  rats  has  had 
no  influence  on  their  growth  (Finney,  Baltimore). 
Another  and  more  important  experiment  where  27 
mentally  deficient  children  at  the  Vineland  farm 
were  fed  with  a  pineal  extract,  led  to  no  noticeable 
effect. 

We  do  know  what  pathological  growths  of  the 
pineal  gland  in  children  will  give  rise  to.  "In  the 
70  cases  on  record  of  tumor  of  the  pineal  gland, 
most  were  in  adults,  but  ten  were  in  boys  below 
the  age  of  puberty;  and  these  all  presented  pre- 
cocious and  pronounced  development  of  the  pri- 
mary and  secondary  sexual  characteristics,  and 
some  a  certain  degree  of  mental  precocity."  (Zan- 
dren) ;  which  points  to  the  presence  of  a  hormone 
that  regulates,  in  some  way,  the  sex  life. 

Dr.  Frederick  Tilney,  in  his  book  1  gives  us  an 

1  Frederick  Tilney  and  H.  A.  Riley:  The  Form  and  Functions 
of  the  Central  Nervous  System  (P.  B.  Hoeber,  New  York,  1921). 


143       GLANDS  IN  HEALTH  AND  DISEASE 

excellent  example  of  a  case  of  pineal  disease.  The 
patient,  a  boy  of  eight,  had  suffered  from  recurrent 
headaches  since  his  sixth  year.  In  his  eighth  year 
his  headaches  had  become  more  severe  and  he  had 
suffered  from  vomiting  attacks.  "His  vision  was 
not  so  good  as  it  had  been,  and  upon  advice  he  be- 
gan to  wear  glasses.  During  his  eighth  year  he 
grew  rapidly  until  he  had  reached  the  height  of  five 
feet  three  inches.  He  was  as  large  as  a  boy  of  14. 
In  addition  to  his  increase  in  stature  his  pubic  hair 
made  its  appearance  and  reached  full  development. 
His  external  genitalia  became  as  large  as  those  of 
an  adult  and  his  sexual  functions  were  fully  estab- 
lished. His  voice  underwent  transition  and  be- 
came much  deepened.  During  this  time,  however, 
he  suffered  from  repeated  headaches  and  his  vision 
progressively  failed. 

"Upon  examination  by  an  oculist  he  was  told 
that  he  had  progressive  optic  atrophy.  He  was 
admitted  to  the  hospital  because  of  his  severe  head- 
aches and  vomiting.  At  this  time  his  vision  was 
practically  gone.  Shortly  after  admittance  to  the 
hospital  he  was  seized  with  a  convulsion  which 
lasted  for  half  an  hour.  After  this  convulsion  he 
never  recovered  consciousness  but  lapsed  into  a 
somnolent  condition  in  which  he  remained  for  sev- 
eral weeks,  at  the  end  of  which  time  he  had  a  sec- 
ond convulsion  and  died  a  few  days  later. 

"Upon  examination  at  the  time  of  his  entrance 


PINEAL  143 

into  the  hospital  the  following  observations,  among 
others,  were  made:  The  patient  gave  evidence  of 
slight  loss  of  volitional  control  in  both  legs  and 
arms.  Although  a  child  of  eight  years  he  looked 
a  boy  of  15  or  16  both  in  size  and  development.  The 
mental  state  of  the  patient  was  difficult  to  estimate. 
He  seemed  precocious  in  certain  particulars  but 
definitely  retarded  in  others.  He  had  been  unable 
to  attend  school  because  of  his  headaches  and  for 
this  reason  his  actual  rating  could  not  be  made. 

"Furthermore,  on  his  admittance  to  the  hospital 
he  was  suffering  from  such  extreme  headaches  that 
only  the  statement  of  his  parents  could  be  depended 
on  in  estimating  his  age.  The  spinal  fluid  on  lum- 
bar puncture  appeared  to  be  under  increased  ten- 
sion, but  it  was  negative  to  all  special  tests.  The 
blood  and  urine  were  also  negative.  The  lesion  in 
this  case  was  a  brain  tumor.  Evidence  of  the  focus 
of  the  lesion  was  afforded  by  the  precocious  somatic 
(pertaining  to  the  framework  of  the  body)  devel- 
opment and  precocious  sexual  development  and 
growth.  The  optic  atrophy  and  blindness,  together 
with  headaches,  convulsions,  somnolence  and  death, 
can  be  accounted  for  by  a  growth  involving  the 
pineal  gland  in  such  a  way  as  to  compromise  the 
aqueduct  of  Sylvius  (a  passage  which  connects  the 
third  and  fourth  ventricle  or  cavity  of  the  brain. 
The  pineal  is  connected  with  the  roof  of  the  third 
ventricle)  and  thus  give  rise  to  an  internal  hydro* 


144       GLANDS  IN  HEALTH  AND  DISEASE 

cephalus  ("water  in  the  head";  an  enlargement  of 
the  head).  This  explains  the  visual  as  well  as  the 
motor  disturbances  in  the  case. 

"The  essential  clinical  features  of  the  disease 
are: 

1.  Precocious  development  and  differentiation 
of  the  external  genitalia,  the  premature  appear- 
ance of  the  axillary  (pertaining  to  the  arm-pit) 
and  pubic  hair. 

2.  Precocious  development  of  the  sex  functions. 

3.  Precocious   abnormal    growth    of   the   long 
bones,  producing  a  stature  of  abnormal  develop- 
ment. 

4.  The  appearance  of  signs  of  internal  hydro- 
cephalus,  including  visual  disorder,  headache,  vom- 
iting, with  choked  disk  or  optic  atrophy. 

5.  The  absence  of  all  other  motor  or  sensory 
symptoms." 

.MAMMARY  GLAND 

I  can  do  no  better  than  quote  Professor  Bayliss, 
who  has  critically  analyzed  the  various  views  ad- 
vanced as  to  the  growth  of  the  gland  in  pregnancy 
and  the  accompanying  secretion  of  milk.  "The 
growth  of  this  organ  is  closely  connected  with  that 
of  the  uterus  (womb)  in  pregnancy,  so  that  it  is 
not  surprising  to  find  that  the  growth  is  affected 


MAMMARY  GLAND  145 

by  a  hormone  produced  in  the  corpus  luteum  ("yel- 
low body"  in  the  ovary  that  grows  for  some  time 
after  impregnation  of  the  ovum).  .  .  .  The  sec- 
ond stage,  associated  with  secretory  activity  in  the 
later  period  of  pregnancy,  is  independent  of  the 
corpus  luteum.  It  has  been  shown  by  Mackenzie 
that  the  gland  is  not  under  the  influence  of  the 
nervous  system,  but  that  extracts  of  various  or- 
gans, injected  into  the  blood  current  of  a  cat  in 
lactation,  cause  secretion  of  milk. 

"The  organs  found  active  were  the  pituitary 
body,  the  corpus  luteum,  the  pineal  body,  the  in- 
voluting uterus  (the  return  of  the  uterus  to  normal 
size  after  child  is  born),  and  the  mammary  gland 
itself.  The  pituitary  body  is  by  far  the  most  active. 
The  fetus  (the  child  in  the  womb  after  the  third 
month.  Before  that  time  it  is  called  the  embryo 
and  placenta  (organ  in  uterus  that  establishes  con- 
nection between  mother  and  child)  produce  hor- 
mones which  inhibit  the  gland. 

"Further  analysis  of  the  action  of  pituitary  ex- 
tract was  made  by  Hammond.  The  effect  is  said 
not  to  be  due  to  pressing  out  of  milk  by  contraction 
of  muscle  in  the  ducts  .  .  .  the  daily  yield  of  goats 
was  found  to  be  only  slightly  increased  by  injec- 
tions, so  that  pituitary  extract  seems  to  act  by 
setting  free  the  constituents  of  milk,  rather  than 
by  causing  increased  formation.  .  .  ." 


146      GLANDS  IN  HEALTH  AND  DISEASE 

KIDNEY 

Experiments  to  prove  that  the  kidney  elaborates 
an  internal  secretion  have  been  of  so  conflicting  a 
kind,  that  references  to  them  would  yield  little  in- 
formation and  much  confusion.  The  curious- 
minded  may  be  referred  to  BiedFs  book  (see  Bibli- 
ography).1 

1  Skin.  Lately  Dr.  Doege,  writing  in  the  Wisconsin  Medical 
Journal  (August,  1921),  discusses  the  evidence  in  favor  of  the 
view  that  the  skin  has  an  internal  as  well  as  an  external  secretory 
function.  There  seems  to  be  an  intimate  connection  between 
the  ductless  glands  and  the  skin.  "Perhaps  the  most  familiar 
examples  are  the  appearance  of  myxedema  with  the  loss  of 
thyroid  function;  the  dependence  of  certain  skin  eruptions  or 
pigmentations  on  the  sex  glands,  pregnancy,  puberty  and  the 
climacteric  period;  the  appearance  of  the  bluish  discoloration  of 
the  skin  in  Addison's  disease,  an  affection  of  the  adrenals. 
Again,  the  fact  that  many  infectious  diseases,  such  as  measles, 
diphtheria,  smallpox,  spotted  fever,  and  syphilis  run  their  course 
with  an  essential  involvement  of  the  skin  is  certainly  not  without 
deeper  significance,  and  points  to  the  probable  fact  that  the  skin 
performs  an  important  function  in  the  overcoming  of  these 
affections.  .  .  ." 


CHAPTER  X 

THE  RELATION  OF  THE  DUCTLESS  GLANDS 
TO  ONE  ANOTHER 

The  function  of  the  hormones  generated  by  the 
ductless  glands  is  to  coordinate  the  various  activi- 
ties of  the  body.  That  there  should  exist  a  close 
relationship  between  any  one  ductless  gland  and 
any  other  or  a  group  of  others,  is  what  might  be 
expected,  but  the  difficulty  in  proving  beyond  all 
question  such  relationships  is  great.  This  chapter, 
then,  should  be  read  with  reserve;  what  is  related 
here  Is  meant  to  be  suggestive  and  no  more.  But 
this  chapter,  like  one  or  two  others  following  it, 
will,  I  trust,  also  serve  as  handy  summaries  of 
much  that  has  been  discussed  in  previous  pages. 

The  eminent  French  physiologist,  Gley,  writes: 
"The  connections  between  the  various  glands  are 
one  of  the  fundamental  facts  maintained  by  the 
doctrine  of  internal  secretions,  and  to  deny  them 
would  be  to  deny  a  part  of  the  doctrine  of  internal 
secretions  itself.  But  what  I  criticize  is  the  in- 
sufficiently demonstrated  theory  of  reciprocal  re- 
lations." And  well  he  may;  there  are  no  end  of 

147 


148      GLANDS  IN  HEALTH  AND  DISEASE 

pitfalls  that  must  be  avoided  if  one  is  to  steer  clear 
of  hypotheses  that  are  attractive  and  that  are  based 
on  the  flimsiest  foundation  of  actual  knowledge. 

One  of  the  earliest  attempts  to  give  us  a  concrete 
picture  of  an  inter-relationship  between  the  duct- 
less glands  was  that  due  to  the  Viennese  patholo- 
gists,  Eppinger,  Falts  and  Rudinger  who,  in  1908, 


PAMCfi£AS 

FIG.   1.      THE  RELATIONSHIP  OF  THE  PANCBEAS  TO  THE 
OTHER  DUCTLESS  GLANDS. 

published  a  paper  dealing  with  the  influence  of  the 
thyroid  and  the  adrenals  on  the  activity  of  the  in- 
ternal secretion  of  the  pancreas.  It  was,  in  fact, 
an  attempt  to  summarize  our  knowledge  of  the 
modus  operandi  of  carbohydrate  metabolism. 
Their  views  will  be  understood  by  reference  to  Fig. 
1,  and  more  particularly  to  Fig.  2. 

It  will  be  remembered  that  in  our  discussion  of 
carbohydrate  metabolism  it  was  stated  that  the 
various  carbohydrates,  such  as  starch  and  cane 


[E  RELATION  OF  THE  DUCTLESS  GLANDS 


igar,  after  undergoing  appropriate  simplification 
in  the  digestive  tract  are  stored  in  the  liver  in  the 
form  of  glycogen  ;  and  that  whenever  the  body  needs 
to  expend  energy,  some  of  the  glycogen  is  converted 
into  glucose,  which  in  turn  finds  its  way  to  the 
muscles,  where  some  may  be  resynthesized  into 
glycogen,  but  where  it  is  ultimately  oxidized  OP 


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1 

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1 
1 
1 

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i 
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GLUCOSE 


FIG.    2. 


THE  EFFECT   OF  MOBILIZATION  OF   SUGAR  IN   THE  LIVES. 

-  =  stimulation  ;  —  -  -  =  inhibition 
An  arrow  indicates  the  direction  of  action. 


''burned,"  yielding,  as  final  products,  carbon  di- 
oxide and  water.  All  this  is  a  very  complicated 
process.  There  must  be  a  regulating  or  guiding 
mechanism  involved  to  establish  order  in  the  place 
of  chaos.  We  have  seen  how  a  large  part  of  this 
function  is  taken  over  by  the  pancreas,  and  we  have 
proved  that  it  is  the  internal  secretion  of  the  pan- 
creas that  is  responsible.  We  have  seen,  for  ex- 
ample, how  the  extirpation  of  the  pancreas  re- 
moves a  restraining  hand  from  the  liver,  with  the 


150      GLANDS  IN  HEALTH  AND  DISEASE 

result  that  an  excess  of  glucose  appears  in  the 
blood,  and  finally  in  the  urine,  giving  rise  to  the 
sugar  disease,  diabetes. 

It  would  seem  as  if  the  thyroid,  and  particularly 
the  adrenals,  accelerate  the  conversion  of  glycogen 
to  glucose,  and  that  the  pancreas,  and  perhaps  to 
some  extent  the  parathyroid,  retard  such  a  conver- 
sion. Eppinger  and  his1  colleagues  reached  this 
conclusion  from  studies  of  the  effect  on  protein 
metabolism  of  injecting  adrenaline.  They  found 
that  this  increased  protein  metabolism  (the  amount 
of  protein  digested  and  utilized)  was  the  same  as 
that  seen  in  hyperthyroidism  and  the  opposite  of 
that  produced  by  the  removal  of  the  thyroid  gland. 
On  the  other  hand,  the  pancreas  seems  to  prevent 
the  formation  of  an  excessive  quantity  of  sugar,  for 
we  see  that  such  an  excessive  quantity  is  produced 
when  the  pancreas  is  removed.  As  for  the  para- 
thyroid, the  general  feeling  that  it  tends  to  neutral- 
ize thyroid  activity  has  made  some  investigators 
class  it  on  the  side  of  the  pancreas.  These  actions 
are  shown  in  Fig.  2. 

Fig.  1  shows  that  the  pancreas,  thyroid  and  adre- 
nals, in  addition  to  influencing  sugar  metabolism 
in  the  liver,  influence  the  activity  of  one  another. 
Thus  the  thyroid  and  adrenals  excite  one  another 
to  activity,  whereas  the  thyroid  and  the  pancreas, 
and  the  adrenals  and  pancreas,  inhibit  one  an- 
other's activity. 


RELATION  OF  THE  DUCTLESS  GLANDS  151 


These  views — particularly  the  one  referring  to 
adrenal  function — have  been  strenuously  opposed 
by  Gley  in  France  and  Stewart  in  this  country. 
Professor  Stewart's  work  will  again  be  referred 
to  in  a  later  chapter  (see  p.  165).  Here  it  may  be 
said  that  he  presented  evidence  to  prove  that  adren- 


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THYMUS 


(/l/ler    Paton) 
FIG.  3.     THE  POSSIBLE  INTEB-EELATIONSHIPS  OF  THE  DUCTLESS  GLANDS. 

=  stimulation ; =  inhibition 

An  arrow  indicates  the  direction  of  action. 

aline  is  not  essentially  concerned  in  experimental 
hyperglycemias  (excess  of  sugar  in  the  blood), 
since  hyperglycemia  is  obtained  in  rabbits  which 
have  survived  double  adrenalectomy.  It  is  con- 
cluded that  the  mobilization  of  sugar,  of  which  ex- 
perimental hyperglycemias  are  an  expression,  is 
not  mediated  through  the  secretion  of  the  adren- 
als. 
Fig.  3  is  a  more  extensive  diagram  to  show  the 


152      GLANDS  IN  HEALTH  AND  DISEASE 

interrelationships  of  the  ductless  glands.  Let  it 
be  emphasized  again  that  the  diagram  is  far  from 
exact,  because  our  knowledge  is  so  incomplete. 
Where  no  connection  between  glands  is  shown,  it 
does  not  follow  that  none  exists,  but  that  so  far 
none  has  been  found  to  exist.  Where  a  connec- 
tion is  shown,  we  merely  mean  to  imply  that  the 
weight  of  opinion  is  in  favor  of  such  a  view,  not  that 
it  is  necessarily  the  correct  view.  Let  us  discuss 
the  meaning  of  the  diagram,  taking  up  each  gland 
in  turn. 

Pituitary  (A)  and  sexual  glands. — Hypopitui- 
tarism  often  gives  rise  to  absence  of  secondary 
sexual  characteristics.  In  a  woman  it  may  show 
itself  by  absence  of  pubic  hair,  and  by  arrested 
development  of  the  breasts.  On  the  other  hand, 
castration  results  in  an  enlargement  of  the  pitui- 
tary. 

That  growth  depends  upon  the  pituitary  has 
long  been  known.  Growth  is  very  largely  com- 
pleted at  puberty.  This  would  explain  why  most 
women  are  smaller  than  men,  since  the  former 
reach  the  stage  of  puberty  before  the  latter. 

In  conformity  with  the  idea  that  the  pituitary 
and  the  sexual  glands  are  intimately  related,  it  has 
been  shown  that  feeding  tadpoles  with  extracts  of 
the  anterior  lobe  of  the  gland  accelerates  sexual 
development  ( Goetsch. ) 

(B)  And  thyroid. — The  removal  of  the  thyroid 


THE  EELATION  OF  THE  DUCTLESS  GLANDS  153 

results  in  the  enlargement  of  the  pituitary,  and 
vice  versa.  Both  the  pituitary  and  the  thyroid 
seem  to  stimulate  the  sexual  glands  in  the  same 
direction.  If  either  is  removed,  not  only  does  the 
animal  fail  to  grow  properly,  not  only  is  there  an 
arrested  development  of  the  mind  and  a  tendency 
towards  adiposity,  but  the  sexual  organs  remain 
undeveloped. 

As  showing  the  parallelism  in  action  of  the  thy- 
roid and  the  pituitary  in  certain  instances,  the  in- 
teresting experiment  has  been  performed  of  feed- 
ing thyroidectomized  rats  with  "tethelin,"  the  sub- 
stance isolated  by  Kobertson  from  the  anterior 
lobe  of  the  pituitary:  a  beneficial  effect  on  the 
growth  of  the  animals  was  observed.  Are  we  to 
assume  that  under  certain  conditions  tethelin  can 
take  the  place  of  the  thyroid  hormone? 

Thyroid  (A)  and  pituitary. — See  under  pitui- 
tary. 

(B)  and  sexual  glands. — Kemoval  of  the  thyroid 
stops  the  growth  of  the  sexual  glands.     Castra- 
tion, however,  does  not  seem  to  have  much  influ- 
ence on  the  thyroid,  though  it  has  been  stated  that 
hyperactivity  of  the  latter,  in  the  shape  of  exoph- 
thalmic goiter,  is  not  uncommon. 

(C)  and  thymus. — Conflicting  results. 

(D)  and  parathyroids. — At  one  time  the  para- 
thyroids were  regarded  as  adjuncts  of  the  thyroid; 
now  the  view  is  quite  firmly  established  that  the 


154      GLANDS  IN  HEALTH  AND  DISEASE 

parathyroid  is  an  independent  organ,  and  that  it 
and  the  thyroid  may  be  regarded  as  displaying  re- 
ciprocating actions. 

(E)  and  adrenals. — The  work  of  Cannon  and 
others  tends  to  show  that  these  two  stimulate  one 
another's  activity.  Hyperthyroidism,  such  as  is 
found  in  Graves's  disease,  is  said  to  increase  the 
adrenaline  in  the  blood,  and  hypothyroidism  les- 
sens the  activity  of  the  adrenals.  The  adrenals 
stimulate  the  production  of  sugar  from  glycogen, 
and  it  is  supposed  that  the  thyroid  also  acts  in  this 
way  (see  Fig.  2) .  This  view  advanced  by  Eppinger 
and  his  associates  in  Vienna,  is  based  on  experi- 
ments which  show  that  the  removal  of  the  thyroid 
makes  adrenaline  less  effective  in  bringing  about 
glycosuria.  Professor  Underbill,  of  Yale,  disagrees 
with  this  view.  We  shall  see  in  a  subsequent  chap- 
ter (p.  165)  that  Professor  Stewart,  of  Western 
Eeserve  University,  has  also  quite  a  number  of 
criticisms  to  offer. 

)  and  pancreas. — We  have  many  conflicting 
theories.  It  has  been  said  that  the  diabetes  pro- 
duced in  an  animal  by  removing  its  pancreas,  can 
be  prevented  by  also  removing  its  thyroid.  If  this 
unlikely  view  is  correct,  then  the  two  glands  show 
reciprocal  actions. 

Adrenals  (A)  and  thyroid. — See  latter. 
J(B)  and  pancreas. — Conflicting.     Kemoval   of 
the  pancreas  produces  sugar  in  the  urine  (glyco- 


THE  RELATION  OF  THE  DUCTLESS  GLANDS  155 

suria).  On  the  other  hand,  addition,  or  rather  in- 
jection of  adrenaline  does  the  same.  Hence  the 
view  that  the  two  act  reciprocally.  Direct  proof 
has  not  been  forthcoming. 

(C)  and  sexual  glands. — Conflicting.  It  is  said 
that  "in  cases  of  sexual  precocity  the  adrenal  cor- 
tex is  much  enlarged." 

Thymus  (A)  and  thyroid. — See  the  latter.  ' 

(B)  and    parathyroids. — Uhlenhuth,     of    the 
Kockefeller  Institute,  is  responsible  for  the  state- 
ment that  the  thymus  secretes  a  tetany-producing 
substance,  the  action  of  which  is  neutralized  by  the 
parathyroids.    This  needs  confirmation. 

(C)  and  sexwal  glands. — The  removal  of  the  thy- 
mus in  early  life  brings  about  the  development  of 
the  sexual  glands.    It  does  seem  as  if  the  function 
of  the  thymus  in  early  life  is  to  retard  the  onset  of 
puberty. 


CHAPTER  XI 

THE  INFLUENCE  OF  THE  DUCTLESS  GLANDS 
ON  GROWTH  AND  METABOLISM 

These  questions  have  been  discussed  in  the  vari- 
ous portions  of  the  book  dealing  with  the  pathology 
of  the  subject.  The  essential  features  may  be 
brought  together  in  this  chapter. 

It  has  been  shown  that  castration  in  early  life 
may  lead  to  abnormal  growth  of  the  skeleton.  On 
the  other  hand,  the  removal  or  atrophy  of  the  thy- 
roid, pituitary,  and  presumably  the  thyrnus,  leads 
to  arrested  growth  (the  cretin  is  an  example). 
Where  the  pituitary  and  (perhaps)  the  thymus 
are  overactive,  we  get  excessive  growth  (gigantism 
and  acromegaly  are  types). 

Whether  the  other  ductless  glands  influence 
growth  is  not  clear. 

When  we  come  to  the  influence  of  the  glands  on 
metabolism — on  the  various  reactions  that  go  on 
within  the  body — we  find  that  the  ductless  glands 
are  of  great  importance.  The  thyroid  is  the  fore- 
most metabolic  regulator  of  the  body.  We  have 
already  seen  how  the  metabolic  rate  is  accelerated 

166 


INFLUENCE  OF  THE  DUCTLESS  GLANDS    157 

in  hyper-thyroidism  and  retarded  in  hypo-thyroid- 
ism.  It  has  already  been  shown  how  the  pan- 
creas, the  adrenals  and  probably  the  thyroid,  di- 
rectly influence  carbohydrate  metabolism.  In  pro- 
tein metabolism — in  the  assimilation  and  general 
utilization  of  meat,  proteins  of  milk  and  eggs,  for 
example — we  have  reasons  to  believe  that  the  thy- 
roid, pituitary,  adrenals  and  the  sexual  glands 
stimulate,  and  the  pancreas  and  the  parathyroids 
inhibit  such  metabolism.  That  metabolic  studies 
are  of  great  value  in  the  diagnosis  of  ductless  glan- 
dular diseases  is  well  illustrated  in  diseases  con- 
nected with  the  thyroid  (see  p.  40). 


CHAPTER  XII 

THE  NERVOUS  SYSTEM  AND  THE  DUCTLESS  GLANDS 

The  work  of  Cannon  of  Harvard,  Crile  of  West- 
ern Reserve  University,  and  the  war  experiences 
of  many  doctors,  more  particularly  in  cases  of 
"shell-shock,"  have  emphasized  the  possibly  close 
connection  between  certain  phases  of  nervous  dis- 
order and  the  derangement  of  the  ductless  glands. 
Let  us  in  the  first  instance  review  very  briefly  some 
of  the  glandular  diseases  that  are  accompanied  by 
nervous  effects,  and  we  can  then  take  up  the  work 
of  Cannon  and  others  in  some  detail. 

Diseases  of  the  thyroid  come  first  in  order.  We 
have  already  seen,  in  discussing  this  subject,  how 
a  hyperthyroidism,  as  exemplified  in  exophthalmic 
goiter,  not  only  increases  the  metabolic  rate,  but 
affects  the  emotions.  Irritability,  hasty  speech,  at- 
tacks of  laughing  and  crying,  and  a  general  rest- 
lessness,— all  this  accompanied  by  a  tremor,  and  a 
rapid  heart  beat,  point  to  a  mental  as  well  as  a 
physical  attack.  In  fact,  the  close  connection  be- 
tween hyperthyroidism  and  the  mental  state  of  the 
patient  is  such  that  an  interesting  discussion  has 

158 


THE  NERVOUS  SYSTEM  159 

r  arisen  as  to  whether  the  origin  of  the  disease 
o  be  laid  at  the  door  of  "nerves,"  whose  rupture 
ys  havoc  with  the  thyroid,  or  at  that  of  the  lat- 
,  which  in  turn  affects  the  "nerves."    An  edi- 
Lal  in  Endocrinology   (1917)   has  this  to  say: 
le  work  of  Cannon  demonstrates  how  complete 
;he  cycle,  and  how  difficult  it  is  in  a  given  case 
tc  ascertain  whether  the  original  cause  was  psychi- 
cal or  material.    In  no  disease  is  this  more  evident 
than  in  Graves's  disease  (which,  you  will  remem- 
ber, is  a  common  form  of  hyperthyroidism ) .   Here 
a  succession  of  nervous  shocks  may  excite  the  adre- 
nals until  the  thyroid  is  put  into  action,  and  hyper- 
thyroidism arises.     But  again  the  stimulation  of 
the  vagus  (nerve  responsible  for  sensation  and  mo- 
tion) may  come  from  so  material  a  source  as  a 
uterine  myoma  (a  tumor  of  the  womb)   or  other 
pelvic  structure — as  Hertzler  points  out.    But  the 
outcome  is  the  same:   the  thyroid  becomes  stimu- 
lated  until   the  threshold   becomes   permanently 
lowered." 

That  the  origin  may  be  a  nervous  one  seems  rea- 
sonably clear  from  the  experiences  of  the  war.  Dr. 
Cobb,  a  captain  in  the  Koyal  Army  Medical  Corps, 
writes :  "It  is  a  well-known  fact  that  the  syndrome 
which  we  have  hitherto  called  'hyperthyroidism' 
is  frequently  met  with  among  the  cases  of  func- 
tional neuroses  which  arrive  at  the  base  hospitals 
.  .  .  the  exophthalmos  is  not  often  marked,  but 


160      GLANDS  IN  HEALTH  AND  DISEASE 

the  fine  tremor,  moist  skin,  tachycardia  (rapid 
tion  of  the  heart),  prominent  thyroid,  and  me 
irritability  are  all  present.  The  brisk  reactio] 
any  emotional  excitement,  with  exaggeration 
those  features,  shows  that  the  mental  elemen 
not  negligible.  Furthermore,  any  one  who  has 
any  lengthy  experience  of  this  class  of  sold 
patient  will  agree  that  his  mental  outlook  is  mi 
edly  similar  to  that  of  the  civilian  patient  with 
ophthalmic  goiter." 

In  hypothyroidism,  as  in  the  cretinous  chuu, 
and  in  the  adult  suffering  from  myxedema,  we  go 
from  the  extreme  of  rapidity  in  action  and  thought 
(hyperthyroidism)  to  complete  sluggishness  and 
mental  apathy.  The  child  coordinates  poorly;  it 
learns  to  talk  late  in  years — sometimes  it  never 
passes  beyond  the  stage  of  inarticulate  sounds;  it 
learns  to  sit  and  to  walk  late.  The  adult  loses  all 
reaction  to  strong  stimuli  and  resembles  the  hiber- 
nating animal. 

Professor  Falta  states  that  the  English  Myxe- 
dema Commission  "found  the  apathy  character- 
istic of  myxedema  to  be  absent  in  three  of  109 
cases.  This  may  develop  relatively  early,  and  in 
the  light  cases  may  consist  in  a  sluggishness  of 
movement,  in  a  retardation  of  the  psychic  func- 
tions, in  an  inability  to  form  rapid  conclusions, 
and  in  a  slowing  and  monotony  of  speech.  Mag- 
nus-Levy, the  German  physiologist,  claims  that 


THE  NERVOUS  SYSTEM  161 

even  in  the  light  cases  the  'capability  of  reacting 
to  strong  stimuli'  is  lost.  The  speech  may  be  mark- 
edly slowed,  'as  if/  writes  the  [late]  Dr.  Meltzer, 
'the  speech  mechanism  were  frozen  in.'  Charcot, 
the  French  neurologist,  compares  such  patients  to 
hibernating  animals. 

"The  English  Commission  found  among  the 
myxedema  patients  investigated  by  them  that  18 
suffered  from  illusions,  16  from  hallucinations,  and 
16  from  frank  psychosis.  The  psychoses  belong  to 
various  types,  although  the  melancholoid  condi- 
tions predominate.  The  symptoms  of  the  psychosis 
often  develop  simultaneously  with  those  of  myxe- 
dema, and  vanish  after  thyroid  therapy  has  been 
instituted,  to  reappear  again  when  the  therapy  is 
discontinued." 

The  researches  of  Cannon,  referred  to  above, 
tend  to  show  that  the  adrenals — and  more  particu- 
larly one  of  their  hormones,  adrenaline, — are 
closely  associated  with  the  mental  state  of  the  per- 
son. The  close  connection  between  the  action  of 
adrenaline  and  that  of  the  sympathetic  system  has 
been  discussed  in  the  chapter  on  the  adrenals.  We 
must  now  take  up  Cannon's  work  in  some  detail. 

The  researches  of  Professor  Cannon. — Professor 
Cannon,  of  Harvard,  working  in  conjunction  with 
a  number  of  his  pupils  ( among  whom  must  be  men- 
tioned de  la  Paz,  Shohl,  Wright,  Washburn,  Ly- 
man,  Nice,  Gruber,  Osgood,  Gray  and  Mendelhall), 


162       GLANDS  IN  HEALTH  AND  DISEASE 

has  brought  forward  evidence  to  show  that  at  times 
of  emotional  excitement,  pain  or  asphyxia  (suffo- 
cation), an  increased  secretion  of  adrenaline  takes 
place.     "Adrenal   secretion   has  previously   been 
proved  to  be  subject  to  sympathetic  stimulation 
(see  page  83) ;  and  as  excitement,  pain  and  as- 
phyxia were  conditions  well  recognized  as  accom- 
panied by  sympathetic  activity    (manifested,  for 
example,  by  inhibition  of  digestive  functions),  an 
attendant  adrenal  secretion  was  naturally  to  be  ex- 
pected.   In  a  series  of  papers  which  follow  the  first 
two  in  1911,  experiments  were  described  showing 
that  adrenal  secretion  was  serviceable  in  lessening 
muscular  fatigue  and  in  accelerating  coagulation 
(clotting)  of  the  blood.     It  was  pointed  out  that 
excitement,   pain   and  asphyxia   were  conditions 
which  in  natural  existence  would  commonly  be  as- 
sociated with  struggle,  and  the  adrenal  secretion, 
which  accompanies  these  three  states,  would  be 
useful  in  great  muscular  effort." 

Cannon  criticized  l>y  Professors  Stewart  and 
Gley. — Stewart,  of  Western  Eeserve  University, 
Cleveland  (working  in  conjunction  with  his  chief 
assistant,  Dr.  Eogoff),  and  Gley,  of  the  College  de 
France,  Paris,  have  seriously  questioned  Cannon's 
interpretations.  From  his  own  work  Stewart 
draws  three  conclusions,  each  one  of  which  helps 
to  explain  a  discrepancy,  and  all  three  of  which 
tend  to  throw  confusion  into  the  camps  of  Cannon's 


THE  NERVOUS  SYSTEM  163 

followers:  In  the  first  place,  the  discharge  of 
adrenaline  is  continuous;  secondly,  the  amount  of 
this  substance  in  any  animal  is  approximately  con- 
stant ;  thirdly,  the  supposed  variation  is  dependent 
on  the  rate  at  which  the  blood  flows  through  the 
veins.  Keeping  these  views  in  mind,  Stewart  finds 
that  neither  in  pain,  nor  in  asphyxia,  nor  in  emo- 
tional excitement,  can  any  increased  secretion  of 
adrenaline  be  detected. 

An  experiment  ~by  Professor  Cannon. — Segments 
of  rabbit  intestine  were  placed  in  cylinders  and 
these  filled  with  samples  of  blood  taken  from  the 
lumbo-  (pertaining  to  the  loins)  adrenal  veins. 
The  blood  was  taken  before  and  after  stimulation 
of  the  central  end  of  the  sciatic  nerve.  "Normal 
blood  removed  before  stimulation  of  the  central  end 
of  the  sciatic  nerve  caused  no  inhibition  of  the 
rhythmically  contracting  intestinal  segment, 
whereas  that  removed  afterwards  produced  a 
marked  relaxation.1  The  conclusion  was  drawn 

aln  the  chapter  on  the  adrenal  glands  we  stated  that  there 
were  two  accepted  methods  for  the  estimation  of  adrenaline, — 
the  one  a  physiological,  and  the  other  a  chemical  method.  The 
physiological  method  is  the  more  sensitive,  and  for  the  extremely 
minute  quantities  of  the  substance  with  which  we  are  here  deal- 
ing, the  physiological  method  is,  at  present,  the  only  one  that 
yields  results.  The  principle  employed  is  one  -which  depends 
upon  the  fact  that  a  portion  of  an  organ,  such  as  the  uterus  or 
the  intestine,  when  bathed  in  blood  or  in  Ringer's  solution — 
containing  a  mixture  of  inorganic  salts  of  a  concentration  similar 
to  that  found  in  blood — will  produce  rhythmic  contractions  that 
can  be  made  to  record  on  a  slowly  revolving  drum;  when,  how- 
ever, adrenaline  even  in  the  proportion  of  on»part  in  one  million 


164      GLANDS  IN  HEALTH  AND  DISEASE   , 

that  the  adrenal  glands  are  affected  through  ner- 
vous channels  when  a  sensory  trunk  (the  main 
stem  of  the  nerve)  is  strongly  excited,  and  that 
they  then  pour  their  secretion  into  the  blood 
stream.1 

It  must  be  remarked  that  the  inhibitory  influ- 
ence on  the  beating  intestinal  strip  is  shown  by 
adrenaline,  which  of  course  suggests  that  the  in- 
hibition described  in  this  experiment  is  the  result 
of  an  increased  activity  of  the  adrenals,  with  a 
consequent  increased  production  of  adrenaline. 
This  adrenaline  is  discharged  into  the  blood.  If 

is  added  to  the  solution,  or  when  blood  containing  a  quantity  of 
adrenaline  above  the  trace  that  is  probably  found  normally,  then 
the  tracings  on  the  drum  show  a  sudden  jump.  For  details  we 
must  refer  the  reader  to  any  standard  textbook  of  physiology. 
Stewart's  includes  a  number  of  interesting  practical  exercises. 

1  For  the  benefit  of  some  readers  who  may  desire  more  detailed 
information,  the  following  additional  points  in  Cannon's  pro- 
cedure are  appended:  The  segments  of  rabbit  intestine  were  sus- 
pended lengthwise  in  a  glass  cylinder  through  which  oxygen  waa 
passed.  The  segment,  when  not  surrounded  by  the  blood  to  be 
tested,  was  bathed  in  Ringer's  solution  (see  above).  The  test 
blood,  the  cylinder  and  the  fresh  Ringer's  solution  were  all  kept 
at  body  temperature  in  a  common  bath.  The  blood  to  be  tested 
was  taken  before  and  after  the  experimental  procedures  by  pass- 
ing a  catheter  (a  tubular  surgical  instrument  for  discharging 
fluid  from  a  cavity  of  the  body)  through  an  incision  in  the 
femoral  vein  (referring  to  the  thigh)  into  the  iliac  (the  haunch- 
bone  or  the  flank)  and  thence  into  the  inferior  vena  cava  an- 
terior to  the  entrance  of  the  lumbo-adrenal  veins.  A  thread  tied 
tightly  around  the  catheter  marked  the  point  to  which  it  was 
inserted  and  permitted  reinsertion  to  the  same  point  in  subse- 
quent sampling  of  the  blood.  The  position  of  the  catheter  open- 
ing, which  was  at  one  side,  was  kept  constant  by  attention  to  the 
position  of  the  knot  in  the  thread.  Thus  both  the  control  blood 
and  the  blood  after  stimulation  were  taken  as  -exactly  as  possible 
from  the  same  region. 


THE  NERVOUS  SYSTEM  165 

Professor  Cannon's  theory  is  correct  there  ought 
to  be  more  adrenaline  in  the  blood  after  stimula- 
tion— in  the  above  experiment  the  stimulation  was 
sensory — than  before  stimulation.  His  experiment 
tends  to  show  that  such  is  actually  the  case. 

In  a  similar  manner  Cannon  has  shown  that 
asphyxia  "causes  a  change  in  the  blood  producing 
the  same  effect  as  adrenaline  on  the  beating  in- 
testinal strip,  namely,  inhibition" ;  and  that  emo- 
tional excitement  gives  rise  to  a  similar  phenome- 
non. Hence  the  conclusion  that  stimulation  of  the 
type  described — whether  sensory,!  as  in  pain, 
whether  of  the  nature  of  emotional  excitement,  or 
of  the  nature  of  asphyxia — increases  the  secretion 
of  adrenaline. 

Stewart  and  Rogoff's  criticism. — As  we  shall 
again  refer  to  Professor  Stewart's  work,  we  need 
only  mention  here  one  or  two  points  that  bear 
directly  on  the  technique  employed.  In  a  critical 
review  of  Cannon's  catheter  method,  Stewart  and 
Kogoff  point  out  that  the  results  obtained  by  it  are 
only  valid  if  the  blood  flow  is  assumed  to  be  con- 
stant during  the  whole  experimental  period,  and 
the  method  does  not  permit  any  judgment  on  that 
point.  If  in  the  course  of  an  experiment  the  rate 
of  blood  flow  over  a  particular  region  varies,  then 
the  samples  taken  at  various  intervals  are  not 
strictly  comparable.  They  maintain  that  the  secre- 
tion of  adrenaline  is  not  influenced  by  reflex  stimu- 


166       GLANDS  IN  HEALTH  AND  DISEASE 

lation,  and  that  the  only  way  in  which  the  experi- 
ment would  indicate  an  increased  concentration  of 
adrenaline  in  the  blood  is  if  the  blood  flow  through 
the  adrenal  vessels  were  retarded. 

The  denervated  heart  as  an  indicator  of  adrenal 
secretion. — In  this  method  instead  of  removing 
blood  from  the  body,  the  denervated  heart  is  used 
to  demonstrate  an  increase  of  adrenaline  in  the 
blood.  "In  a  cat  under  urethane,  with  vagi  (nerves 
of  sensation  and  motion)  cut  and  stellate  ganglia 
(referring  to  nervous  matter)  excised,  stimulation 
of  the  central  end  of  the  cut  sciatic  will  cause  the 
heart  rate  to  increase  in  some  instances  as  much  as 
50  beats  per  minute.  .  .  .  The  completely  dener- 
vated heart  can  be  used  as  an  indicator  of  adrenal 
secretion  in  testing  the  influence  of  emotional  ex- 
citement quite  as  well  as  in  testing  the  influence  of 
sensory  stimulation  and  asphyxia.1  The  results 
obtained  with  the  isolated  heart  used  as  an  indi- 
cator of  adrenal  secretion  thus  confirm  in  every 

1  Again  for  the  benefit  of  some  readers  certain  details  should 
be  added.  To  denervate  the  heart  the  stellate  ganglia  are  first 
removed  under  ether  with  aseptic  precautions;  later  the  right 
vagus  nerve  is  severed  below  the  recurrent  laryngeal  branch;  and 
still  later  the  left  vagus  nerve  is  cut  in  the  neck.  The  heart  is 
thus  wholly  disconnected  from  the  central  nervous  system,  and 
any  agency  causing  an  increase  in  the  heart  rate  must  exert  its 
influence  through  the  blood  stream.  With  the  adrenal  glands 
normally  innervated  the  rate  was  217  per  minute  when  the  animal 
was  calm,  and  255  when  excited.  After  the  adrenal  glands  were 
removed  the  rate  when  calm  was  217  and  when  excited  221, — an 
inappreciable  difference. 


THE  NEEVOUS  SYSTEM  167 

respect  the  results  obtained  eight  years  ago  (1911) 
by  the  catheter  method."  (Cannon.) 

Professor  Stewart  objects  again. — One  would  ex- 
pect an  increased  rate  of  the  denervated  heart, 
writes  Professor  Stewart,  when  the  central  end  of 
the  sciatic  or  the  peripheral  of  the  splanchnic  nerve 
is  stimulated,  for  "it  is  obviously  dependent  upon 
the  better  flow  through  the  coronary  vessels'' ;  and 
the  increased  rate  of  blood  flow  through  the  de- 
nervated heart  increases  the  amount  of  adrenaline 
passing  a  given  area  in  unit  time.  He  objects  to 
the  use  of  any  organ  in  the  body  as  an  indicator  of 
adrenal  secretion  when  asphyxia  is  employed  as 
a  stimulus,  "because  asphyxia  may  be  expected  to 
alter  the  reactivity  of  the  test  object  to  adrenaline, 
making  it,  for  example,  more  sensitive."  "We  never 
supposed/'  he  continues,  "that  it  was  possible  to 
use  in  one  observation  an  asphyxiated  test  object 
and  in  the  comparison  observation  the  same  object 
with  unobstructed  respiration,  or  to  assume  that 
if  there  was  any  difference  in  reactions,  it  must  be 
due  to  a  difference  in  the  rate  of  output  of  adrena- 
line; the  conditions  of  the  test  object  itself  being 
of  no  moment." 

When  two  such  redoubtable  adversaries  as  Can- 
non and  Stewart  appear  in  the  field,  it  is  not  to  be 
expected  that  either  the  one  or  the  other  can  hope 
for  a  quick,  decisive  victory.  Both  are  masters  in 


168       GLANDS  IN  HEALTH  AND  DISEASE 

the  field  of  experimental  physiology,  and  both  are 
thinkers  untrammelled  by  any  standardized  meth- 
ods of  thought.  For  every  "no"  of  Stewart,  Cannon 
finds  a  "yes."  To-day  as  little  as  ever  before  is 
Cannon  disposed  to  agree  with  his  colleague  that 
the  adrenal  effects  may  be  accounted  for  on  the 
basis  of  greater  flow,  or  of  altered  distribution  of 
the  blood.  Cannon  hits  back  with  the  same  weap- 
ons that  Stewart  employs:  he  does  not  question 
the  results  but  he  does  question  the  methods.  "The 
work  of  Stewart  and  Kogoff  was  admirably  quanti- 
tative in  character,  but  it  was  done  under  experi- 
mental conditions  which  could  not  afford  informa- 
tion regarding  the  normal  secretion  of  the  adrenal 
glands  or  the  natural  conditions  which  affect  that 
secretion.  This  conclusion  applies  to  all  inferences 
as  to  the  nature  of  adrenal  activity  which  they 
have  based  upon  the  employment  of  the  pocket 

method.1 

t 

JThe  "pocket"  refers  to  a  pocket  in  the  inferior  vena  cava. 
The  pocket  was  made  by  opening  the  abdominal  cavity,  clamping 
the  vena  cava  immediately  above  the  iliacs,  then  clamping  the 
renal  veins,  emptying  the  cava  segments  by  stripping  it  upwards, 
and  placing  a  clamp  on  the  vessel  above  the  entrance  of  the 
lumbo-adrenal  veins.  Any  small  branches  of  the  cava  segment 
were  tied.  The  pocket  thus  formed  was  allowed  to  fill  with 
blood  from  the  adrenal  veins,  and  the  blood  was  either  allowed 
to  pass  into  the  general  circulation  by  removal  of  the  clamp  of 
the  inferior  vena  cava,  or  was  withdrawn  and  tested  outside  the 
body  on  preparations  of  rabbit  uterus  and  intestine. 

Professor  Cannon's  comment  is  characteristic:  "Either  be- 
cause the  opening  of  the  abdomen  produces  a  secretion  unsur- 
passable by  reflex  stimulation,  or  because  that  operation  abolishes 
abdominal  reflexes,  the  influence  of  sensory  stimulation  on  the 


THE  NERVOUS  SYSTEM  169 

Professor  Cannon's  views  as  to  the  function  of 
adrenaline. — This  brings  us  to  Cannon's  "emer- 
gency theory."  In  times  of  stress — as  when  a  per- 
son suffers  pain,  or  is  in  an  agitated  state  of  mind 
— a  chemical  factor,  in  the  shape  of  adrenaline, 
cooperates  with  nervous  factors  in  an  attempt  to 
meet  the  emergency  and  not  be  overcome  by  it. 
That  is  why,  according  to  Cannon,  we  find  an  in- 
creased output  of  adrenaline  in  times  of  stress. 

But  we  must  be  careful  not  to  misinterpret  this 
view  of  Cannon's.  "The  concept  of  an  emotion 
may  be  expressed  either  in  psychological  terms  of 
subjective  experience  or  in  physiological  terms  of 
bodily  change.  Adrenal  secretion  is  not  essential 
to  the  subjective  experience  of  strong  emotion. 
Adrenaline  has  its  effect  peripherally,  on  outlying 
viscera.  An  assumption  that  subjective  feeling  de- 
pends on  circulating  adrenaline  involves  support- 
ing the  view  that  emotion  as  a  psychological  state 
is  the  consequence  of  visceral  changes.  I  have,  in 
fact,  definitely  argued  against  this  view.  If  the 
critics  of  the  emergency  theory  conceive  emotion 
as  bodily  change,  they  will  find  in  Cannon's  con- 
sideration of  the  interrelations  of  emotions  the 
point  emphasized  that  it  is  the  sympathetic  division 

adrenal  glands  is  not  manifested.  There  is  little  wonder,  there- 
fore, that  Stewart  and  Rogoff,  who  alone  have  employed  the 
pocket  method,  with  its  attendant  severe  abdominal  operation 
and  repeated  manipulation  of  the  abdominal  contents,  failed  to 
obtain  the  positive  results  which  have  been  obtained  by  all  other 
observers." 


170       GLANDS  IN  HEALTH  AND  DISEASE 

of  the  autonomic  system  which  is  the  primary 
'agency  in  mobilizing  the  bodily  forces  in  times  of 
great  fear  or  rage.  .  .  .  These  suggestions  imply 
coordination  of  chemical  and  nervous  factors,  but 
not  a  dependence  of  the  nervous  factors  on  the 
chemical." 

Professor  Cannon's  book. — Under  "Bibliography" 
towards  the  end  of  the  book  I  shall  include  suffi- 
cient references  to  Cannon's  papers  so  that  the 
reader  who  desires  it  may  get  inspiration  from  the 
original  source;  but  I  cannot  resist  the  temptation 
of  dwelling,  if  only  for  a  minute  or  two,  on  his 
book,  "Bodily  Changes  in  Pain,  Hunger,  Fear  and 
Kage,"  a  sequel  to  an  earlier  and  no  less  celebrated 
volume,  "The  Mechanical  Factors  in  Digestion." 
It  is  a  record  of  an  attempt  to  investigate  certain 
psychological  reactions — some  of  which  have  al- 
ready been  discussed  in  these  pages — by  means  of 
recognized  methods  in  experimental  physiology. 
The  writer  is  strongly  convinced  that  the  great  ad- 
vances in  psychology  are  not  to  be  expected  so 
much  from  the  psychologist  who  is  an  arm-chair 
philosopher  or  who  dabbles  in  "efficiency"  tests,  as 
from  those  men  whose  training  has  been  in  the  ex- 
perimental sciences  primarily, —  in  chemistry, 
physics  and  biology.  I  do  not  of  course  mean  that 
the  philosopher  has  no  contribution  to  make ;  I  do 
not  belong  to  the  ultra-scientific  school  which  takes 
it  for  granted  that  it,  and  it  alone,  can  lay  claim  to 


THE  NEKVOUS  SYSTEM  171 

the  mantle  of  glory  and  achievement;  but,  com- 
paratively speaking,  I  think  that  the  physiologist 
who  investigates  psychological  phenomena  has 
more  to  offer  us  than  the  metaphysical  speculator 
who  turns  psychologist. 

In  the  early  portion  of  the  book  we  are  intro- 
duced to  the  physiological  methods  for  determining 
adrenaline,  and  are  then  shown  that  emotional 
excitement  gives  rise  to  adrenaline  in  the  blood  in 
amounts  sufficient  to  be  detected,  though  the 
amounts  may  be  less  than  a  few  parts  per  million. 
One  of  the  experiments  dealing  with  emotional 
excitement  is  to  bring  a  dog  and  cat  near  one  an- 
other. The  cat  exposed  to  the  barks  of  the  dog 
shows  an  increased  adrenaline  output. 

The  fact  that  injection  of  adrenaline  into  the 
body  of  an  animal  gives  rise  to  a  glycosuria,  or  an 
increase  of  sugar  in  the  urine  (a  form  of  what  is 
commonly  called  "diabetes"),  and  the  fact  that 
emotional  excitement  induces  an  increased  output 
of  adrenaline,  leads  directly  to  the  next  step :  can 
glycosuria  be  called  forth  by  emotional  excite- 
ment? Cannon  finds  that  it  can.  One  experiment 
is  of  exceptional  interest.  Of  25  members  of  the 
Harvard  University  football  squad  whose  urine 
was  examined  immediately  after  a  most  exciting 
contest  during  the  season  of  1913,  12  showed  sugar. 
After  a  day  or  two, — after  a  complete  rest,  that  is — 
the  sugar  disappeared  completely. 


GLANDS  IN  HEALTH  AND  DISEASE 

Of  what  value  are  the  sugar  and  the  adrenaline 
that  are  poured  into  the  blood  during  emotional 
excitement?  We  have  already  indicated  the  an- 
swer in  several  portions  of  the  book.  Let  Professor 
Cannon  speak.  "The  adrenaline  plays  an  essential 
r61e  in  calling  forth  stored  carbohydrate  from  the 
liver,  thus  flooding  the  blood  with  sugar.  .  .  . 
Since  the  fear  emotion  and  the  anger  emotion  are, 
in  wild  life,  likely  to  be  followed  by  activities  (run- 
ning or  fighting)  which  require  contraction  of 
great  muscular  masses  in  supreme  and  prolonged 
struggle,  a  mobilization  of  sugar  in  the  blood  might 
be  of  signal  service  to  the  laboring  muscles.  .  .  . 
Adrenaline  helps  in  distributing  the  blood  to  the 
heart,  lungs,  central  nervous  system  and  limbs, 
while  taking  it  away  from  the  inhibited  organs  of 
the  abdomen;  it  quickly  abolishes  the  effects  of 
muscular  fatigue;  and  it  renders  the  blood  more 
readily  coagulable.  These  remarkable  facts  are, 
furthermore,  associated  with  some  of  the  most 
primitive  experiences  in  the  life  of  the  higher  or- 
ganisms, experiences  common  to  all,  both  man  and 
beast — the  elemental  experiences  of  pain  and  fear 
and  rage  that  come  suddenly  in  critical  emergen- 
cies." 

In  connection  with  these  investigations,  Cannon 
discusses  and  connects  the  excitements  and  ener- 
gies of  competitive  sport;  the  frenzy  and  endurance 


THE  NERVOUS  SYSTEM  173 

in  ceremonial  and  other  dances ;  and  the  fierce  emo- 
tions and  struggles  in  battle. 

The  latter  portion  of  the  book  is  devoted  to  the 
nature  of  hunger,  which  has  roots  similar  to  those 
of  fear  and  anger.  Hunger  is  shown  to  be  the  direct 
result  of  contractions  of  the  alimentary  canal,  a 
fact  amply  verified  by  the  elaborate  researches  of 
.Professor  Carlson,  of  the  University  of  Chicago. 
That  in  fever  hunger  should  be  absent  seems  logical 
because  "infection,  with  systemic  involvement,  is 
accompanied  by  a  total  cessation  of  all  movements 
of  the  alimentary  canal.  Boldireff  observed  that 
when  his  dogs  were  fatigued  the  rhythmic  contrac- 
tions failed  to  appear.  Being  'too  tired  to  eatf  is 
therefore  given  a  rational  explanation." 

The  closing  chapter  of  the  book  pleads  for  moral 
substitutes  for  warfare.  The  key  to  Cannon's 
views  is  presented  through  the  medium  of  William 
James  who,  in  proposing  a  moral  equivalent  for 
war,  wrote:  "We  must  make  new  energies  and 
hardihoods  continue  the  manliness  to  which  the 
military  mind  so  faithfully  clings.  Martial  virtues 
must  be  the  enduring  cement;  intrepidity,  con- 
tempt of  softness,  surrender  of  private  interest, 
obedience  to  command,  must  still  remain  the  rock 
upon  which  states  are  built.  .  .  .  The  martial  type 
of  character  can  be  bred  without  war.  Strenuous 
honor  and  disinterestedness  abound  elsewhere. 


174       GLANDS  IN  HEALTH  AND  DISEASE 

Priests  and  medical  men  are  in  a  fashion  educated 
to  it,  and  we  should  all  feel  some  degree  of  it  im- 
perative if  we  were  conscious  of  our  work  as  an 
obligatory  service  to  the  state.  We  should  be 
owned,  as  soldiers  are  by  the  army,  and  our  pride 
would  rise  accordingly.  We  could  be  poor,  then, 
without  humiliation,  as  army  officers  now  are. 
The  only  thing  needed  henceforth  is  to  inflame  the 
civic  temper  as  past  history  has  inflamed  the  mili- 
tary temper." 

It  is  ten  years  since  James  wrote  these  words, 
and  during  those  years  much  has  happened  to  make 
this  advice  even  more  imperative.  Neither  the  vic- 
torious Peace  of  Versailles,  nor  yet  the  Washington 
Conference  for  the  Limitation  of  Armaments,  holds 
out  immediate  relief  from  military  dominance. 
One  wonders  what  kind  of  calamity  the  gods  can 
send  us  so  that  we  may  be  awakened  before  the 
Great  Flood  sweeps  us  forever  from  off  this  globe. 

Dr.  Crile's  researches. — Dr.  Crile,  the  famous 
Cleveland  surgeon,  has  advanced  a  theory  regarding 
shock  and  exhaustion  which  deserves  treatment  in 
this  chapter  for  two  reasons:  first,  because  in  his 
theory  the  adrenals  play  an  active  part;  and  sec- 
ondly because  of  the  success  he  has  had  in  the  clini- 
cal application  of  his  theory. 

Shock — of  which  the  varieties  of  shell-shock  de- 
scribed during  the  late  war  are  types — is  character- 
ized by  a  loss,  to  a  large  extent,  of  deliberate  ac- 


THE  NERVOUS  SYSTEM  175 

tion.  "The  man  in  acute  shock  or  exhaustion," 
writes  Crile,  "is  able  to  see  danger,  but  lacks  the 
normal  muscular  power  to  escape  from  it ;  his  tem- 
perature may  be  subnormal  but  he  lacks  the  nor- 
mal power  to  create  heat ;  he  understands  words  but 
lacks  the  normal  power  of  response."  He  cannot 
transform  potential  into  kinetic  energy.  Herein 
lies  the  key  to  the  situation.  We  also  see  why  Crile 
talks  of  the  "kinetic  theory  of  shock." 

Let  us  dwell  on  this  "kinetic  theory"  for  a  min- 
ute. Various  stimuli  arouse  various  associations; 
the  latter  may  be  of  the  nod  or  injurious  type,  or 
the  bene  or  beneficial  type.  "All  of  life  is  made  up 
of  bene-  and  noci-associations,  and  the  constant 
effort  of  the  race  and  the  individual  is  to  increase 
the  former  and  decrease  the  latter,  to  develop  an 
environment  which  shall  be  as  free  as  possible  from 
noci-associations, — to  reach  a  state  of  anoci-associa- 
tion"  Anoci-associaMon  is  the  title  given  to  one 
of  Dr.  Crile' s  very  suggestive  books.  In  it  he  shows 
how  the  percentage  of  successful  surgical  cases 
may  be  increased  by  a  treatment  which  applies  the 
principles  of  anoci-association  before,  during  and 
after  the  operation. 

"The  difference  between  normal  processes  and 
shock  is  that  of  intensity,  not  of  kind.  From  these 
premises  it  becomes  obvious  that  the  exclusion  of 
both  traumatic  and  emotional  stimuli  will  wholly 
prevent  the  shock  of  surgical  operations."  To  ac- 


176       GLANDS  IN  HEALTH  AND  DISEASE 

complish  the  desired  result,  the  conditions  which 
produced  the  shock  are  ameliorated  or  eliminated, 
and  the  circulation  is  supported.  For  the  details 
the  reader  must  be  referred  to  the  book.  One  fur- 
ther quotation  must  suffice.  "By  an  assuring  pre- 
operative  treatment;  by  the  definite  dulling  of  the 
nerves  through  the  administration  of  a  narcotic; 
by  a  non-suffocating  odorless  anesthetic ;  by  a  local 
anesthetic  to  cut  off  all  afferent  impulses  during 
the  course  of  the  operation ;  by  a  second  local  anes- 
thetic of  lasting  effect  to  protect  the  patient  during 
the  painful  postoperative  hours ;  by  gentle  manipu- 
lation and  sharp  dissection, — by  the  combination  of 
all  these  methods — the  patient  is  protected  from 
damage  from  every  factor  excepting  those  which 
exist  in  the  diseased  condition  from  which  relief 
is  sought."  * 

*How  successful  this  method  is  may  be  gauged  from  the  fact 
that  Dr.  Crile  can  operate  on  a  patient  suffering  from  exophthal- 
mic goiter  without  materially  increasing  his  pulse  rate.  "It  was 
in  large  measure  the  study  of  the  preoperative  and  postoperative 
course  of  cases  of  Graves's  disease  which  led  to  the  enunciation 
of  the  kinetic  theory  of  shock  and  the  development  of  the  shock- 
less  operation.  ...  By  the  extension  of  employment  of  anocia- 
tion  and  asepsis,  the  mortality  in  the  last  6,261  operations  at 
Lakeside  Hospital  (Cleveland)  has  been  reduced  to  1.6  per  cent. 
Our  series  have  included  58  colostomies  and  resections  of  the 
rectum  and  large  intestine  for  cancer,  with  one  death,  and  70 
resections  of  the  stomach  and  gastro-enterostomies  for  cancer 
and  ulcer  of  the  stomach,  with  one  death.  Anociation  and 
asepsis  have  made  possible  a  series  of  227  consecutive  thyroid- 
ectomies  and  180  consecutive  ligations,  that  is,  407  conseci5tive 
thyroid  operations  for  hyperthyroidism  without  a  death.  These 
are  not  selected  cases.  No  patient  was  rejected  and  many  were 
dying.  Among  the  last  500  thyroidectomies,  there  have  been  five 


THE  NERVOUS  SYSTEM  177 

Man  is  surrounded  by  noci-associations,  and  he 
is  forever  attempting  to  reach  a  state  of  anoci-asso- 
ciation.  An  example  of  this  is  the  attempt  made  by 
a  body  when  infected  to  produce  an  anti-toxin. 
Under  certain  conditions — as  a  result  of  fear, 
worry,  physical  injury,  infection,  hemorrhage,  ex- 
cessive muscular  exertion,  starvation,  insomnia — 
an  excessive  amount  of  energy,  stored  in  the  form 
of  potential  energy,  is  discharged;  this  "excessive 
conversion  of  potential  into  kinetic  energy  in  re- 
sponse to  adequate  stimuli"  leads  to  shock.  Such 
is  the  "kinetic  theory  of  shock,"  which  further 
states  that  the  lesions  of  shock  are  to  be  found  in 
the  cells  of  the  brain,  in  the  liver,  and — what  inter- 
ests us  most  in  this  chapter — in  the  adrenals. 

"In  our  laboratory,"  writes  Dr.  Crile,  "we  found 
cytologic  changes  in  the  adrenals  in  exhaustion 
from  any  cause,  including  insomnia ;  these  changes 
being  more  marked  in  the  cortex  than  in  the  me- 
dulla. Apparently  adrenaline  alone  can  cause  the 
brain  greatly  to  increase  its  work.  By  cross-circu- 
lation experiments,  we  have  found  that  adrenaline 
causes  increased  activity  of  the  central  vasomoter 
mechanism.  Not  only  can  adrenaline,  as  Cannon 
has  shown,  cause  all  the  basic  phenomena  of  exer- 
tion, emotion,  infection,  etc.,  but  it  also  causes 
brain  cell  lesions  identical  with  those  produced  by 

deaths,  a  mortality  rate  of  one  per  cent.,  and  among  the  last  500 
ligations,  two  deaths." 


178      GLANDS  IN  HEALTH  AND  DISEASE 

exertion,  emotion,  infection,  etc.  .  .  .  The  injection 
of  adrenaline  causes  an  immediate  increase  in  the 
conductivity  of  the  brain  to  above  normal,  followed 
by  a  later  decrease  to  below  the  normal;  more- 
over, adrenaline  causes  an  immediate  increase  in 
the  temperature  of  the  brain,  as  evidenced  by 
thermo-couple  measurements." 

The  work  of  Drs.  Steivart  and  Rogoff. — In  dis- 
cussing Dr.  Cannon's  work  we  have  also  referred, 
a  number  of  times,  to  that  of  Drs.  Stewart  and 
Rogoff,  if  only  because  the  latter  two  are  equally 
eminent  authorities,  and  mainly  because  they  com- 
bat much  of  what  Cannon  has  to  say.  The  nature 
of  this  work  and  the  limitations  of  space  will  pre- 
vent us  from  giving  details,  but  the  reader  who  is 
interested  may  refer  to  the  list  of  references  to  their 
work  that  is  included  in  the  bibliography. 

Adrenaline  is  the  big  theme.  Is  there  or  is  there 
not  an  increase  of  this  substance  when  an  animal  is 
emotionally  aroused?  We  have  already  suggested 
that  Stewart's  answer  is  in  the  negative,  and  that 
he  explains  Cannon's  positive  results  by  finding 
fault  with  the  method  employed,  and  with  the  way 
in  which  the  results  were  interpreted. 

It  will  also  be  remembered  that  Cannon  makes 
much  of  the  fact  that  not  only  does  adrenaline  give 
rise  to  a  hyperglycemia,  but — what  might  be  ex- 
pected if  what  Cannon  asserts  is  true — so  do  the 
emotions  when  aroused  sufficiently;  for,  according 


THE  NERVOUS  SYSTEM  179 

to  Cannon,  the  emotions  arouse  the  adrenals  to 
particular  activity,  an  increased  quantity  of  adrena- 
line then  appears  in  the  blood,  and  this  in  turn 
interferes  with  normal  carbohydrate  metabolism 
to  such  an  extent  that  an  abnormal  quantity  of 
sugar  finds  its  way  into  the  blood,  giving  rise  to 
hyperglycemia. 

"We  have  recently,"  write  Drs.  Stewart  and 
Kogoff,  "studied  the  question  whether  adrenaline 
secretion  of  the  adrenals  is  indispensable  for  the 
production  of  certain  experimental  hyperglycemias. 
The  majority  of  previous  investigations  have  suf- 
fered from  the  defect  that  they  were  carried  out, 
if  not  on  practically  moribund  animals,  at  least  on 
animals  still  under  the  effects  of  a  serious  opera- 
tion. This  undoubtedly  is  the  chief  reason  for  the 
astonishing  lack  of  uniformity  in  the  results. 
Working  with  animals  (cats)  in  which  the  adrena- 
line secretion  was  abolished  or  reduced  to  an  in- 
significant fraction  of  the  normal  by  removal  of 
one  adrenal  and  section  of  the  nerves  of  the  other 
(an  operation  which  does  not  preclude  the  contin- 
ued life  of  the  animal  in  good  health),  we  were 
able  to  show  that  two  forms  of  experimental  hyper- 
glycemia— that  produced  by  ether  and  that  pro- 
duced by  asphyxia — are  as  readily  obtained  in  the 
absence  of  adrenaline  secretion  as  when  the  adre- 
nals have  not  been  interfered  with."  What,  then, 
have  the  adrenals  got  to  do  with  hyperglycemia? 


180       GLANDS  IN  HEALTH  AND  DISEASE 

Neither  have  Drs.  Stewart  and  Kogoff  less  sharp 
criticism  to  offer  with  regard  to  the  alleged  con- 
nection of  adrenaline  with  the  condition  known  as 
"shock,"  a  subject  we  have  discussed  in  the  last  few 
pages.  "A  large  though  quite  undeserved  place  has 
been  occupied  in  clinical  literature  of  shock  and 
allied  conditions  by  adrenal  insufficiency,  or  one 
or  other  of  its  aliases.  There  is  no  evidence  that 
any  notable  change  occurs  in  the  adrenaline  output 
in  either  direction."  The  experimental  methods  of 
producing  shock  in  dogs  and  cats — by  exposing  and 
manipulating  the  intestines,  by  partial  occlusion  of 
the  inferior  vena  cava,  by  hemorrhage  and  by  "pep- 
tone" injection — led  to  a  permanent  lowering  of 
blood  pressure ;  but  the  rate  of  output  of  adrenaline 
after  the  blood  pressure  had  been  permanently 
lowered  was  found  to  be  the  same  as  before  the 
lowering  of  the  blood  pressure,  "within  the  limits 
of  error  of  the  methods  used  for  assaying  the 
adrenaline." 

Professor  Stewart's  caustic  pen  hits  at  the 
"clinical  endocrinologist"  even  more  than  at  the 
experimental  physiologist.  He  writes :  "In  reading 
the  papers  by  'clinical  endocrinologists/  especially 
the  French  and  Italians,  the  physiologist  can 
scarcely  escape  the  feeling  that  here  he  has  broken 
through  into  an  uncanny  fourth  dimension  of  medi- 
cine, where  the  familiar  canons  and  methods  of 
scientific  criticism  are  become  foolishness,  where 


THE  NERVOUS  SYSTEM  181 

fact  and  hypothesis  are  habitually  confounded, 
and  'nothing  is  but  what  is  not.' ? 

Such  criticisms,  coming  from  a  critic  whose  aim 
is  to  create  rather  than  to  destroy,  are  of  the  utmost 
value  to  the  progress  of  the  science.  It  deserves 
prominent  place  in  a  book  such  as  this,  where  the 
attempt  is  made  never  to  confound  fact  with 
fancy.1 

The  sexual  glands  and  the  nervous  system. — That 
the  sexual  glands  and  the  nervous  system  are 
closely  related  is  only  too  obvious  from  the  many 
studies  on  the  sex  problem,  and  by  the  more  direct 
method  of  castration  in  animals  and  men.  Much 
of  all  this  has  already  been  discussed  in  another 
chapter  (page  94).  Less  pronounced  connections 
between  the  glands  and  the  nervous  mechanism  are 
noticeable  in  diseases  of  the  pituitary  and  the  para- 
thyroids. 

*I  have  just  (December,  1921)  returned  from  the  annual  meet- 
ing of  the  Federation  of  American  Societies  for  Experimental 
Biology,  held  this  year  at  Yale  University.  These  meetings  were 
much  enlivened  by  papers  by  Stewart  and  Cannon.  Both  are  not 
only  first-class  scholars  but  excellent  debaters,  and  their  annual 
tilts  are  eagerly  looked  forward  to.  This  eagerness  on  the  part 
of  the  onlookers  to  enjoy  the  fun  brought  forward  this  remark 
from  Dr.  Stewart:  "We  are  not  waiting  for  Dr.  Cannon  to  say 
something  and  then  to  jump  at  him;  we  merely  seek  the  truth, 
just  as  I  know  he  does."  This  but  brought  laughter  and  knowing 
looks.  Dr.  Carlson,  the  Chicago  physiologist,  whose  sympathies 
are  evidently  more  with  Stewart  than  with  Cannon,  brought 
down  the  house  with  this  remark:  "I  am  glad  to  find  that 
Cannon  no  longer  pins  his  faith  to  the  adrenals  alone;  for  that 
he  and  the  Society  are  to  be  congratulated  on  a  return  to 
'normalcy.' " 


182      GLANDS  IN  HEALTH  AND  DISEASE 

Psycho-analysis. — It  would  be  strange  that  in 
the  treatment  of  those  most  complex  of  phenomena 
that  group  themselves  under  mental  disorders,  con- 
flicts should  not  arise  between  the  enthusiastic  en- 
docrinologist  and  the  Freudian  disciple;  the  one 
with  his  eye  to  the  ductless  glands  as  the  source  of 
much  evil,  and  the  other  with  his  emphasis  on  the 
repression  of  the  emotions.  Professor  Gushing,  in 
an  article  on  "Psychic  disturbances  associated  with 
disorders  of  the  ductless  glands,"  leans  towards 
the  former  school,  though  he  is  not  blind  to  the 
merits  of  psycho-analysis.  He  writes :  "The  vari- 
ous neuroses  (nerve  diseases)  and  asthenias  (loss 
of  strength)  may  result  primarily  as  the  result  of 
some  disturbance  of  internal  secretion  which  paves 
the  way  for  the  dreams,  symbolisms  and  other 
manifestations  dissected  by  the  psycho-analyst. 
...  It  is  quite  probable  that  the  psycho-pathology 
of  every-day  life  hinges  largely  upon  the  effect  of 
ductless  gland  discharges  upon  the  nervous  system. 
This  is  particularly  worthy  of  consideration  in  the 
study  of  child  psychology  in  its  relation  to  puberty 
and  adolescence,  especially  in  those  individuals  in 
which  there  is  some  underlying,  possibly  inherited, 
/  functional  deviation  in  the  chemistry  of  the  inter- 
nal secretion.  .  .  ." 

Shell-shoclc.-^-This  brings  us  to  the  last  phase 
of  our  subject,  that  of  shell-shock.  ( The  reader  is 
advised  to  re-read  Dr.  Crile's  views  on  shock,  page 


THE  NERVOUS  SYSTEM  183 

174.)  We  may  perhaps  preface  our  remarks  by 
saying  that  the  strenuous  life  led  by  the  individual 
in  the  city,  especially  by  the  "hustler/'  and  espe- 
cially by  the  "hustler"  with  a  weak  resistive  ca- 
pacity, may  cause  a  nervous  breakdown  which  is 
not  far  removed  from  shell-shock.  Again  we  must 
refer  the  reader  to  Dr.  Crile. 

Shell-shock 

I _ 

I  I.  I 

Transitory  symptoms  Concussions  Psycho-neuroses 


Death  Organic  affection  Functional  affection 


I  I  I 

Hysteria  Psychasthenia  Neurasthenia 


Ductless  glandular  disturbance 


I  I  I 

Hyper-adrenalism      Disfunction  of  sex  glands    Hyperthyroidism 

Shell-shock  has  been  defined  as  "the  condition 
which  follows  exposure  to  the  forces  generated  by 
the  explosion  of  powerful  shells  in  the  absence  of 
any  visible  injury  to  the  head  or  spine."  It  may 
result  in  a  speedy  recovery,  in  a  definite  concussion, 
or  in  the  appearance  of  symptoms  of  the  psycho- 


184       GLANDS  IN  HEALTH  AND  DISEASE 

it 
nettroses.     If  either  of  the  latter  two  symptoms 

makes  its  appearance,  it  may  be  in  connection 
with  a  disturbance  of  one  or  more  of  the  ductless 
glands.1  Dr.  Cobb  has  drawn  up  an  attractive 
classification  which  is  given  above. 

The  classification  of  nervous  disorders  is  due  to 
Beard,  Charcot,  Mobius  and  Janet.  Janet  divided 
psycho-neuroses  as  shown  in  the  table.  "Hysteria" 
represents  a  typical  mental  disintegration,  whereby 
there  is  a  splitting  of  mental  processes,  so  that  two 
separate  and  unconnected  streams  exist  in  the  mind 
(for  example,  anesthenia,  amnesia  [loss  of  mem- 
ory], paralysis) ;  "psychasthenia"  refers  to  cases 
characterized  by  phobias  (persistent  insane  dread 
or  fear),  hesitations,  doubts,  anxieties;  while 
"neurasthenia"  refers  to  cases  showing  a  prepon- 
derance of  symptoms  referable  to  physical  exhaus- 
tion (fatigue,  indigestion,  disturbances  of  excre- 
tion, etc.). 

1Clemence  Dane,  the  author  of  "A  Bill  of  Divorcement,"  now 
playing  in  New  York,  has  drawn  a  powerful  and  moving  picture 
of  the  shell-shocked  soldier.  Allan  Pollock,  who  interprets  the 
part,  was  himself  through  this  living  hell.  The  interpretation  is 
a  triumph  of  the  actor's  skill. 


CHAPTER  XIII 

ORGANOTHERAPY 

The  treatment  of  ductless  glandular  diseases  by 
means  of  extracts  of  appropriate  glands  dates  back 
to  Brown-Sequard's  investigations  in  1889,  and 
Brown-Sequard  merely  revived  the  old  "humoral" 
view  of  disease.  Hippocrates  advocated  the  efficacy 
of  various  organs,  and  Hahnemann,  the  originator 
of  homeopathy,  built  up  a  subdivision  of  the  sub- 
ject, isopathy,  which  dealt  with  diseased  organs, 
and  with  their  cure  by  the  administration  of  fresh 
organs.  Is  your  liver  out  of  joint?  Then  we  will 
prescribe  the  liver  of  a  wolf.  Have  you  a  tremor? 
The  brain  of  a  hare  will  put  you  on  your  feet  again. 
Are  you  a  sufferer  from  dyspepsia?  Take  the  lung 
of  a  fox  and  you  will  get  well.  Is  your  stomach 
misbehaving?  Take  rennin. 

The  "humoral"  philosophy  throve,  made  many 
converts,  did  some  good  and  very  much  mischief, 
and  gradually  died  out.  Brown-Sequard  brought  it 
to  light  again;  but,  let  us  add,  in  quite  a  modern 
form,  and  with  reasons  for  its  revival  drawn  from 
the  knowledge  of  the  nineteenth  and  not  the  ninth 

185 

7? 


186       GLANDS  IN  HEALTH  AND  DISEASE 

century.  One  may  truly  say  of  him  that  he  is  the 
founder  of  the  conception  of  ductless  glandular 
function  as  we  understand  it  to-day. 

Poor  Brown-Sequard!  In  glorious  company 
with  other  ill-received  or  unrecognized  geniuses,  he 
became  the  laughing-stock  of  scientific  Paris.  He 
described  to  his  audience  how  he  had  administered 
to  himself  testicular  extracts,  and  how,  as  a  result 
of  this  administration,  his  vigor  and  youthful  de- 
sires and  appetites  had  returned.  (In  1889  when 
this  announcement  was  made  Brown-Sequard  was 
70  years  old.)  The  Academy  laughed,  and  Paris 
and  the  other  capitals  of  Europe  made  the  most  of 
a  sensational  piece  of  news. 

Was  there  any  foundation  for  Brown- Sequard's 
claim?  From  what  we  know  to-day,  not  very  much. 
Not  even  the  most  enthusiastic  exponents  of  "reju- 
venation" by  means  of  the  sexual  glands  advocate 
such  a  procedure. 

If  the  use  of  testicular  extract  proved  discourag- 
ing, it  did  not  prevent  the  use  of  extracts  from 
other  glands  that  produce  an  internal  secretion. 
And  then  came  the  truly  remarkable  discovery  that 
in  myxedema  and  cretinism,  examples  of  hypothy- 
roidism,  the  administration  of  thyroid  extracts 
brought  cures — cures  that  lasted,  to  be  sure,  only 
so  long  as  treatment  with  the  extract  was  contin- 
ued. This  discovery  made  those  who  had  scoffed 
at  Brown-Sequard  revise  their  opinion  of  that  illus- 


OEGANOTHEEAPY  187 

trious  Frenchman.  A  new  impetus  was  given  the 
subject,  and  glandular  treatment  became  the  hope 
of  a  world  full  of  maladies. 

Despite  an  enormous  amount  of  work,  it  cannot 
be  said  that  we  have  accomplished  much  with  glan- 
dular extracts  beyond  their  use  in  thyroid  disease. 
Pituitary  extracts  have  had  a  measure  of  success 
in  pituitary  disorders,  but  not  comparable  to  the 
corresponding  extract  from  the  thyroid  when  ap- 
plied to  cases  of  hypo-thyroidism. 

With  a  persistence  worthy  of  some  admiration, 
glandular  advocates,  failing  to  get  results  with  any 
one  extract,  tried  each  one  of  the  others  in  turn. 
Still  without  result,  they  adopted  pluriglandular 
treatment — that  is  to  say,  treatment  by  the  use  of 
extracts  from  several  glands.  It  cannot  be  said 
that  these  methods  yielded  any  better  results. 

Now  the  question  may  very  naturally  be  asked, 
why  should  thyroid  extract  be  of  service  in  hypo- 
thyroidism,  and  why  should  extracts  from  other 
glands  be  of  so  little  service  in  other  diseases  due 
to  glandular  insufficiency?  We  do  not  know, 
though  we  can  speculate  as  to  the  cause.  Are  we 
to  assume  that  only  the  thyroid  hormone  is  resistive 
enough  to  escape  all  dangers  and  reach  its  desti- 
nation safely,  whereas  other  hormones  are  de- 
stroyed on  the  way?  1  This  is  not  a  likely  hypothe- 

1  "No  assumption  is  needed  in  this  case  any  longer,  because  we 
now  know  that  thyroxin  is  of  a  very  different  nature  from  any 


188      GLANDS  IN  HEALTH  AND  DISEASE 

sis,  for  even  injecting  directly  into  the  blood — 
the  path  along  which  the  hormones  travel — does  not 
materially  improve  matters.  Or  perhaps  extracts 
other  than  the  thyroid  contain  substances  in  addi- 
tion to  the  liormones  that  are  in  themselves  inju- 
rious to  the  system.  Unfortunately  for  this  theory, 
we  know  that  adrenaline,  100  per  cent,  pure,  repre- 
senting the  adrenal  hormone,  does  not  cure  Addi- 
son's  disease,  a  disease  of  the  adrenals.  Of  course 
it  may  be  said  with  much  force  that  adrenaline  is 
the  hormone  of  but  one  portion  of  the  adrenals,  the 
medulla,  and  that  the  hormone  of  the  cortex  of  the 
gland  has  not  yet  been  isolated ;  so  that  until  this 

other  of  the  constituents  of  the  ductless  glands.  We  know  that 
it  does  not  vary  in  its  amount  in  the  tissues  except  in  a  minor 
degree,  that  it  is  constantly  supplied  and  that  any  single  portion 
of  it  functions  for  as  long  as  seven  weeks  after  administration 
or  after  the  gland  manufactures  it ;  that  is,  it  acts  as  a  catalyst, 
and  it  does  not  come  under  your  definition  of  a  hormone.  It 
acts  in  a  manner  to  increase  the  rate  of  oxidation  within  the 
tissues,  and  we  can  now  picture  the  chemical  changes  occurring 
which  permit  thyroxin  to  function  as  a  catalytic  agent.  None  of 
the  active  constituents  of  the  other  ductless  glands  acts  in  this 
way  in  respect  to  time.  Adrenaline  does  undoubtedly  act  as  a 
catalyst,  increasing  the  rate  of  oxidation  within  the  cells,  but  it 
functions  for  a  very  short  period  of  time.  That,  to  my  mind, 
is  the  explanation  of  why  the  adrenal  and  the  hypophysis  are  so 
closely  related  to  the  nervous  system.  They  are  strictly  emer- 
gency glands  and  their  output  must  be  increased  and  decreased 
on  demand.  They  function  for  a  brief  interval  and  that  is  why 
it  is  impossible  to  administer  them  successfully,  because  only 
relatively  massive  doses  are  given,  interspersed  with  periods  of 
zero  administration.  Thyroxin  is  just  the  reverse  of  this.  It 
does  not  function  immediately  and  lasts  for  as  long  as  five  to 
seven  weeks,  so  that  it  is  not  only  unique  among  the  glands  for 
therapeutic  purposes,  but  it  is  unique  in  its  chemical  proper- 
ties." (E.  C.  Kendall.) 


ORGANOTHERAPY 

is  done,  and  until  the  pure  hormones  from  both 
parts  of  the  gland  are  used,  it  would  be  premature 
to  draw  any  conclusions. 

Perhaps  the  .most  plausible  suggestion  so  far  ad- 
vanced is  that  in  the  preparation  of  a  glandular 
extract,  involving  physical  and  chemical  processes, 
the  chemical  configuration  of  the  hormone  is  pos- 
sibly altered,  and  hence  its  physiological  action  be- 
comes lost.  To  point  to  the  thyroid  extract  as  dis- 
proving this  hypothesis  does  not  hold,  for  the  an- 
swer may  be  made  that  there  is  no  reason  to  sup- 
pose that  all  the  hormones  have  the  same  degree 
of  resistive  power.  The  antiscorbutic  vitamine  is 
more  easily  destroyed  than  the  antirachitic ;  why 
may  this  not  be  true  of  hormones  as  well?  Why 
may  not  one  hormone  fall  a  prey  to  chemical 
agents  more  quickly  than  another? 

Unquestionably  the  next  step  in  our  forward 
march  will  be  the  isolation,  in  a  pure  form,  of  the 
hormones  from  the  pituitary,  the  cortex  of  the  adre- 
nals, the  sexual  glands,  etc.  Until  this  is  done  we 
can  hope  little  more  from  glandular  treatment  than 
what  has  already  been  accomplished.1 

»At  the  recent  (Dec.,  1921)  meeting  of  the  Physiological  So- 
ciety, held  in  New  Haven,  Professor  Macleod,  of  the  University 
of  Toronto,  read  a  paper  on  the  value  of  pancreatic  extracts,  in 
which  he  pointed  out  that  the  blood  sugar  of  a  depancreatized 
dog  could  be  lowered  by  injecting  a  pancreatic  extract,  and  that 
neither  an  extract  of  the  liver  nor  one  of  the  spleen  had  that 
effect.  Though  preliminary  in  character,  the  investigation  i& 
important  and  suggestive. 


CHAPTER  XIV 

PLANT   HORMONES 

The  work  of  Professor  Bottomley,  of  the  Uni- 
versity of  London,  has  made  it  very  probable  that 
vitamines  play  an  important  part  in  the  plant,  as 
well  as  in  the  animal  kingdom.  He  has  even  pre- 
sented some  very  good  evidence  to  show  that  the 
vitamines  found  in  the  animal  world  can 'be  traced 
to  vegetable  sources;  that  though  the  animal  needs 
vitamine,  yet  it  cannot  synthesize  it,  but  must  rely 
on  this  synthesis  being  accomplished  by  plant  cells. 
This  work  of  Bottomley's  has  been  amply  confirmed 
in  many  quarters. 

Similar  problems  present  themselves  when  deal- 
ing with  hormones.  In  the  first  place,  are  there 
plant  hormones  that  are  activators  in  the  sense 
that  the  animal  hormones  are?  And  is  it  possible 
that  the  hormones  in  our  body  are  synthesized  in 
the  plant,  rather  than  in  the  animal  kingdom? 

The  second  question  will  be  disposed  of  first. 
We  know  that  glands  are  factory  centers  of  the 
body.  We  know  that  the  gland  has  the  power  of 
taking  various  materials  from  the  blood,  and  con- 

190 


PLANT  HORMONES  191 

verting  them  into  an  entirely  new  product,  or  prod- 
ucts. The  essential  product  of  a  ductless  gland  is 
its  hormone — at  least,  that  is  the  supposition — and 
this  is  probably  manufactured  by  the  gland.  The 
indirect  proof  we  have  for  this  statement  is  that 
under  normal  conditions  the  hormones  in  the 
body  are  sufficient  in  amount,  or  sufficiently  active, 
to  perform  their  specific  functions;  and  it  is  only 
when  a  pathological  condition  sets  in  that  the 
hormonic  function  is  disturbed. 

You  may  say  that  this  is  not  very  convincing. 
You  may  claim  that  under  normal  conditions  the 
gland  has  the  power  of  removing  the  hormone  from 
the  blood,  and  that  it  no  longer  has  such  power 
under  pathological  conditions.  This  objection  can, 
I  think,  be  met  with  in  this  way:  If  we  examine 
the  constitutional  formula  for  adrenaline,  a  hor- 
mone in  the  adrenals,  or  of  thyroxin,  a  hormone 
in  the  thyroid  gland,  we  shall  see  that  no  food 
we  eat  contains  any  such  substance.  We  do, 
however,  find  that  their  formulas  show  them  to  be 
closely  related  to  certain  substances  that  are  in- 
cluded in  our  diet — or  at  least,  are  formed  in  the 
digestive  tract  as  a  result  of  the  food  we  eat.  For 
example,  the  amino-acid  tryptophane1  shows  cer- 
tain resemblances  to  thyroxin;  hence  the  opinion 
that  one  of  the  possible  reasons  why  tryptophane  is 

1  See   the  chapter   on   Amino-Acids  in   the   author's   book   on 
Vitamines. 


192      GLANDS  IN  HEALTH  AND  DISEASE 

an  essential  acid  is  that  the  body  needs  it  for  the 
manufacture  of  thyroxin;  though  so  far  as  I  know 
no  one  has  as  yet  shown  that  an  increase  of  trypto- 
phane  in  our  diet  increases  the  quantity  of  thyroxin 
in  the  body. 

Now  as  to  the  next  question:  are  there  plant 
hormones?  And  if  so,  do  they  play  a  part  in  the 
plant  kingdom  analogous  to  that  played  by  hor- 
mones in  the  animal  kingdom?  Let  us  quote  Pro- 
fessor Bayliss  on  this  point: 

"Although  there  is  no  such  effective  way  of 
chemical  interchange  in  plants  as  there  is  in  the 
circulating  blood  of  animals,  there  is  distinct  evi- 
dence that  chemical  products  of  one  part  are  able 
to  influence  the  activities  of  other  parts.  The  lat- 
eral roots,  which  normally  grow  horizontally,  can 
be  made  to  grow  vertically  downwards  if  the  main 
root  is  removed.  Errera  investigated,  in  pines,  the 
corresponding  change  of  direction  of  growth  of  a 
branch  into  a  vertical  stem  when  the  apical  bud 
of  the  main  stem  is  removed.  He  suggested  that 
the  apical  bud  of  the  main  stem  forms  some  kind 
of  internal  secretion,  which  prevents  the  upward 
growth  of  the  lateral  shoots  as  long  as  this  apical 
bud  is  present. 

"Keeble  considers  that  such  'chemical  stimu- 
lators' play  a  part  in  the  transfer  of  activity  of 
localized  cambium  cells  to  others  in  their  neighbor- 


PLANT  HOEMONES  193 

hood.  In  the  case  of  Convoluta,  Roscoffensis,  the 
signal  for  the  commencement  of  the  later  phases 
of  development  owes  its  origin  to  the  presence  of  the 
green  algal  cells,  without  whose  concurrence,  prob- 
ably by  the  production  of  a  hormone,  no  kind  of 
artificial  feeding  has  been  found  effective. 

"Mention  may  also  be  made  of  the  substance  ex- 
tracted by  rain  from  grass,  which  has  been  shown 
by  Pickering  to  be  injurious  to  apple  trees.  They 
should  not,  in  fact,  be  surrounded  by  growing  grass, 
as  is  common  in  orchards." 

We  know  that  a  number  of  ethereal  salts,  or,  as 
the  chemist  calls  them,  "esters,"  act  as  accelerators, 
in  the  sense  of  hastening  the  flowering  of  plants  and 
the  ripening  of  fruits ;  and  we  know  further  that  the 
essential  oils  present  in  plants  are  largely  made  up 
of  such  "esters."  As  to  whether  these  essential 
oils  are  manufactured  by  glands  similar  to  those 
existing  in  the  animal  kingdom,  and  as  to  whether 
there  is  any  interrelationship  between  such  glands, 
cannot,  at  present,  be  answered.  It  is  supposed 
that  these  "esters,"  and  substances  other  than 
"esters"  that  act  like  accelerators,  stimulate  en- 
zyme (ferment)  action  in  the  plant,  particularly  in 
the  later  stages  of  its  development.  On  this  basis 
the  many  color  changes  that  take  place  during  the 
ripening  period,  the  autumnal  color  of  leaves,  and 
the  dropping  of  the  leaves  from  the  stem  of  the 


194      GLANDS  IN  HEALTH  AND  DISEASE 

plant,  have  been  explained ;  but  all  this  is,  at  pres- 
ent, largely  fancy  and  little  more.1 

1  Mention  may  here  be  made  of  a  more  direct  experiment  by 
Dr.  Budington,  of  Oberlin  College.  He  experimented  with  sound 
onion  bulbs  which  were  placed  in  a  nutrient  solution  to  which 
small  quantities  of  glandular  extracts — from  the  thyroid,  the 
adrenal  and  the  pituitary — were  added.  A  certain  amount  of 
"retardation"  in  the  growth  of  root  tips  when  thyroid  extract 
was  used,  and  marked  modifications  of  growth  when  iodine  in 
the  form  of  potassium  iodide  was  used,  were  obtained.  "While 
no  general  conclusion  can  be  based  on  experiments  limited  to  a 
single  form,  the  indication  is  that  thyroid  constituents — and  it 
will  be  remembered  that  iodine  is  such  a  constituent — may  in- 
fluence the  role  of  protoplasmic  action  in  cells  other  than  those 
of  animal  tissues." 


REFERENCES 


REFERENCES 

GENERAL.  There  are  a  number  of  books  dealing  with 
the  glands  of  internal  secretion.  A  standard  work  is  that 
by  A.  Biedl:  The  Interned  Secretory  Organs  (William 
Wood  &  Co.,  New  York) .  More  than  100  of  the  600  pages 
are  devoted  to  references  to  the  original  literature.  An- 
other excellent  work  is  S.  Vincent's  Internal  Secretion  and 
the  Ductless  Glands  (Edward  Arnold,  London).  C.  E. 
de  M.  Sajous'  The  Internal  Secretions  and  the  Principles 
of  Medicine  (F.  A.  Davies  Co.,  Philadelphia)  is  an  am- 
bitious work  in  two  volumes.  E.  A.  Schafer,  the  Edin- 
burgh physiologist,  is  the  author  of  The  Endocrine  Organs 
(Longmans,  Green  &  Co.,  London),  which  emphasizes  the 
physiological  rather  than  the  clinical  point  of  view.  On 
the  other  hand,  W.  Falta's  The  Ductless  Glandular  Dis- 
eases (P.  Blakiston's  Son  &  Co.,  Philadelphia)  is  wholly 
clinical.  D.  Noel  Paton  in  The  Nervous  and  Chemical 
Regulators  of  the  Body  (Macmillan  &  Co.,  London)  em- 
phasizes chemical  factors.  For  those  having  a  reading 
knowledge  of  German,  A.  Weil's  Die  Innere  SeTcretiori 
(Julius  Springer,  Berlin)  may  be  recommended,  since  it 
is  both  authoritative  and  up-to-date.  A  very  good  histori- 
cal development  is  given  by  E.  Gley  in  The  Internal  Secre- 
tions (Paul  B.  Hoeber,  New  York;  translated  from  the 
French  by  Maurice  Fishberg).  A  more  recent  book  by 
the  same  author,  who  is  professor  of  physiology  at  the 

197 


198      GLANDS  IN  HEALTH  AND  DISEASE 

College  de  France,  may  be  suggested  to  those  possessing 
a  working  knowledge  of  the  French  language ;  it  is  entitled 
Quatre  Legons  des  Secretions  Internes  (J.  B.  Balliere  et 
Fils,  Paris).  Other  books  dealing  with  internal  secretions 
are  I.  G.  Cobb :  The  Organs  of  Internal  Secretion  (William 
Wood  &  Co.,  New  York)  ;  S.  W.  Bandler:  The  Endocrirws 
(W.  B.  Saunders  Co.,  Philadelphia);  L.  Berman:  The 
Glands  Regulating  Personality  (Macmillan  &  Co.) ;  and 
H.  R.  Harrower:  The  Internal  Secretions  in  Practical 
Medicine  (Chicago  Medical  Book  Co.,  Chicago). 

Among  medical  encyclopedias  that  include  articles  on 
internal  secretions,  two  may  be  mentioned  because  they 
are  recent  productions.  An  article  on  ductless  glands  will 
be  found  in  volume  3  of  The  Oxford  Medicine  (Oxford 
University  Press,  London),  and  another,  in  volume  3  of 
The  Nelson  Loose-Leaf  Living  Medicine  (Nelson  &  Co., 
New  York). 

Books  dealing  with  various  phases  of  medicine  include 
chapters  on  the  ductless  glands.  Some  of  these  are  J.  J.  R. 
Macleod:  Physiology  and  Biochemistry  in  Modern  Medi- 
cine (C.  V.  Mosby,  St.  Louis) ;  R.  Burton-Opitz :  A  Text- 
Book  of  Physiology  (W.  B.  Saunders  &  Co.,  Philadelphia) ; 
A.  P.  Mathews:  Physiological  Chemistry  (William  Wood 
&  Co.,  New  York) ;  L.  Luciani:  Human  Physiology,  vol- 
ume 2  (Macmillan  &  Co.,  London) ;  W.  M.  Bayliss:  The 
Principles  of  General  Physiology  (Longmans,  Green  &  Co., 
London);  W.  H.  Howell:  A  Text-Book  of  Physiology 
.(W.  B.  Saunders  &  Co.,  Philadelphia) ;  W.  G.  MacCallum: 
'A  Text-Book  of  Pathology  (W.  B.  Saunders  &  Co.,  Phila- 
delphia) ;  W.  Osier :  The  Principles  and  Practice  of  Medi- 
cine (D.  Appleton  &  Co.,  New  York) ;  E.  H.  Starling: 


REFERENCES  199 

Principles  of  Humari  Physiology  (Lea  &  Febiger,  Phila- 
delphia) ;  G.  N.  Stewart  :  A  Manual  of  Physiology  (Wil- 
liam Wood  &  Co.,  New  York)  ;  M.  Kahn  :  Functional 
Diagnosis  (W.  F.  Prior  Co.,  Hagerstown,  Maryland)  ;  and 
H.  G.  Wells:  Chemical  Pathology  (W.  B.  Saunders  &  Co., 
Philadelphia). 


VITAMIKES  Ain)  HORMONES.  The  possible  relationship 
or  identity  of  these  two  substances  has  been  urged,  more 
particularly,  by  Voegtlen  and  Myers,  and  by  Butcher 
(American  Journal  of  Physiology,  volume  49,  page  124, 
1919;  Journal  of  Pharmacology  and  Experimental  Thera- 
peutics, volume  13,  page  301,  1919;  and  Journal  of  Bio- 
logical Chemistry,  volume  39,  page  63,  1919).  This  the- 
ory has  met  with  opposition;  see,  for  example,  Anrep  and 
Drummond's  paper  on  "The  Supposed  Identity  of  the 
Water-Soluble  Vitamine  B  and  Secretin"  (Journal  of 
Physiology,  volume  54,  page  249,  1921).  A  possible  con- 
nection between  vitamine  B  and  adrenaline  has  been  sug- 
gested by  MacCarrison  (see  the  Indian  Journal  of  Medical 
Research,  volume  6,  pages  275  and  550,  1919,  and  the 
Proceedings  of  the  Royal  Society,  section  B,  volume  91, 
page  103,  1920).  Kellaway's  paper  on  "The  Effect  of 
Certain  Dietary  Deficiencies  on  the  Suprarenal  Glands" 
(Proceedings  of  the  Royal  Society,  section  B,  volume  92, 
page  6,  1921)  should  also  be  consulted. 

THE  THYROID.  (See  also  the  "general"  references 
above.)  A  number  of  books  dealing  more  specifically  with 
this  gland  have  been  published.  R.  McCarrison's  The 
Thyroid  in  Health  and  Disease  (Balliere,  Tindall  &  Cox, 


200      GLANDS  IN  HEALTH  AND  DISEASE 

London)  may  be  especially  recommended.  A.  Crotti  fe  the 
author  of  the  Thyroid  and  the  Thymus  (Lea  and  Febiger, 
Philadelphia).  Other  books  are  H.  J.  Ochsner:  Surgery 
and  Pathology  of  the  Thyroid  and  Parathyroid  Glands 
(C.  V.  Mosby,  St.  Louis) ;  and  H.  Eichardson:  The  Thy- 
roid and  Parathyroid  Glands  (P.  Blakiston's  Son  &  Co., 
Philadelphia). 

Kendall's  work  on  the  "Isolation  of  the  Iodine  Com- 
pound Which  Occurs  in  the  Thyroid"  will  be  found  in  the 
Journal  of  Biological  Chemistry,  volume  39,  page  125,  and 
volume  40,  page  265,  1919.  His  lecture  before  the  Harvey 
Society  ("The  Chemistry  of  the  Thyroid  Secretion,"  the 
Harvey  Lectures,  1919-1920,  published  by  J.  B.  Lippincott 
Co.,  Philadelphia)  was  a  fine  historical  review  of  the  entire 
work. 

The  subject  of  hyper-thyroidism  has  received  consider- 
able attention  lately.  In  this  connection  the  reader  will 
find  in  W.  M.  Boothby's  article,  "Adenoma  of  the  Thyroid 
with  Hyper-thyroidism"  (Endocrinology,  volume  5,  page  1, 
1921),  a  very  thorough  discussion  of  the  types  of  thyroid 
disease,  with  references  to  the  latest  literature.  H.  R. 
Harrower's  booklet,  Hyperthyroidism  (Glendale,  Califor- 
nia), suffers  from  an  over-enthusiastic  treatment.  The 
favorable  effects  of  surgical  treatment  coupled  with 
"physiologic  rest"  are  advocated  by  C.  W.  Crile  in  "Surgery 
Versus  Roentgen  Ray  in  the  Treatment  of  Hyperthyroid- 
ism" (Journal  of  the  American  Medical  Association,  vol- 
ume 77,  page  1324,  1921). 

With  regard  to  the  subject  of  metamorphosis,  a  very 
exhaustive  review,  with  references  to  the  original  literature, 
is  given  by  J.  F.  Fulton  in  his  article,  "The  Controlling 


REFERENCES  201 

Factors  in  Amphibian  Metamorphosis"  (Endocrinology, 
volume  5,  page  67,  1921).  A  shorter  review  is  that  by 
L.  T.  Hogben  (Science  Progress,  volume  15,  page  303, 
1920).  Jacques  Loeb's  "Natural  Death  and  the  Duration 
of  Life,"  an  article  included  in  B.  Harrow's  Contemporary 
Science  (Boni  &  Liveright,  New  York),  suggests  many 
fascinating  possibilities. 

How  the  determination  of  the  basal  metabolic  rate  helps 
to  diagnose  the  various  types  of  thyroid  disease  is  dis- 
cussed by  a  number  of  physicians  in  a  forthcoming  volume, 
Basal  Metabolism  (Sanborn  Co.,  Boston).  There  are  any 
number  of  individual  articles  dealing  with  basal  metab- 
olism; only  a  few  of  these  can  be  mentioned  here.  See,  for 
example,  F.  G.  Benedict,  Journal  of  the  American  Medical 
Association,  volume  77,  page  247,  1921;  J.  H.  Means, 
Journal  of  the  American  Medical  Association,  volume  77, 
page  347,  1921 ;  W.  M.  Boothby,  Journal  of  the  American 
Medical  Association,  volume  77,  page  252,  1921;  F.  H. 
Lahey,  Boston  Medical  and  Surgical  Journal,  volume  184> 
page  348,  1921;  J.  R.  Murlin,  Science,  volume  54,  page 
196,  1921;  C.  W.  McCarthy,  Journal  of  the  American 
Medical  Association.,  volume  76,  page  978,  1921.  In  vol- 
ume 1  of  the  Oxford  Loose-Leaf  Medicine  (Oxford  Uni- 
versity Press,  London)  will  be  found  Du  Bois'  article  on 
"Clinical  Calorimetry  Methods  of  Study  of  Metabolism." 

With  regard  to  the  prevention  of  simple  goiter  in  man, 
Marine,  and  his  co-worker  Kimball,  are  widely  known  for 
such  studies.  Some  of  their  papers  are  to  be  found  in  the 
Journal  of  the  American  Medical  Association.,  volume  77, 
page  1068,  1921,  and  volume  73,  page  1874,  1919 ;  Ohio 
State  Journal,  October,  1920 ;  Archives  of  Internal  Medi- 


202      GLANDS  IN  HEALTH  AND  DISEASE 

cinef  volume  22,  page  41,  1918,  and  volume  25,  page  661, 
1920;  and  Journal  of  Laboratory  and  Clinical  Medicine, 
volume  3,  page  40,  1917.  A  suggestive  article  by  E.  K. 
Hayhurst,  entitled  "The  Present-Day  Sources  of  Common 
Salt  In  Kelation  to  Health  and  Especially  to  Iodine  Scar- 
city and  Goiter'5  (Journal  of  the  American  Medical  Asso- 
ciation, volume  78,  page  18, 1922),  wherein  it  is  urged  that 
"common  salt  for  dietary  purposes  should  include  not  only 
sodium  chloride  but  also  sodium  iodide,"  should  be  con- 
sulted. 

THE  PARATHYROIDS.  (See  also  the  "general"  references 
above.)  Two  books  that  deal  with  the  parathyroids  as  well 
as  with  the  thyroid  have  already  been  mentioned:  H.  J. 
Ochsner:  Surgery  and  Pathology  of  the  Thyroid  and  Para- 
thyroid Glands  (C.  V.  Mosby,  St.  Louis),  and  H.  Rich- 
ardson: The  Thyroid  and  Parathyroid  Glands  (P.  Blakis- 
ton's  Son  &  Co.,  Philadelphia).  An  exhaustive  account  of 
these  glands,  accompanied  by  a  very  complete  bibliography, 
may  be  found  in  W.  M.  Boothb/s  "The  Parathyroid 
Glands"  (Endocrinology,  volume  5,  page  403,  1921). 
MacCallum  and  Voegtlin  (Journal  of  Experimental  Medi- 
cine, volume  11,  page  118,  1909)  take  up  the  question  of 
the  relation  of  tetany  to  the  parathyroid  glands  and  to 
calcium  metabolism. 

THE  PITUITARY  GLAND.  (See  also  the  "general"  refer- 
ences above.)  The  classical  work  in  English  is  Harvey 
Cushing's  The  Pituitary  Body  and  Its  Disorders  (J.  B. 
Lippincott  &  Co.,  Philadelphia).  W.  Blair  Bell  is  also  the 
author  of  a  book  on  the  pituitary  (William  Wood  &  Co., 


REFERENCES  203 

New  York).  T.  B.  Robertson's  work  on  the  isolation  of  a 
substance  from  the  anterior  lobe  of  the  pituitary  is  set 
forth  in  an  article  in  Endocrinology  (volume  1,  page  24, 
1917). 

THE  ADRENAL  GLANDS.  (See  the  "general"  references 
above,  as  well  as  the  references  listed  under  "the  nervous 
system  and  the  ductless  glands.")  Fine  critical  articles  are 
those  by  Stewart  and  by  Barker  (Endocrinology,  volume  5, 
page  283,  1921,  and  volume  3,  page  253,  1919).  An  ac- 
count of  the  chemistry  of  adrenaline  is  given  by  Abel 
(Johns  Hopkins  Hospital  Bulletin,  volume  9,  page  215, 
1898,  and  volume  12,  page  80,  1901),  Takamine  (Ameri- 
can Journal  of  Pharmacy,  volume  73,  page  523,  1901; 
Journal  of  Physiology,  volume  27,  page  xxix,  1901)  and 
Friedmann  (Beitrdge  zur  chemische  Physiologic,  volume  8, 
page  95,  1906).  Bargees  volume,  The  Simple  Natural 
Bases  (Longmans,  Green  &  Co.,  London)  should  also  be 
consulted. 

THE  ORGANS  OF  REPRODUCTION.  (See  also  the  "gen- 
eral" references  above.)  A  standard  work  is  Marshall's 
Physiology  of  Sex  Reproduction  (Longmans,  Green  & 
Co.,  London).  Steinach's  book,  Verjungung  (Julius 
Springer,  Berlin),  gives  an  excellent  summary  of  the 
author's  researches.  Phases  of  Steinach's  work  are 
discussed  in  the  Journal  of  the  American  Medical  Asso- 
ciation for  Jan.  29,  1921  (page  348),  Aug.  14,  1920 
(page  490),  Aug.  28,  1920  (page  617),  Sept.  11,  1920 
(page  755),  and  Dec.  25,  1920  (page  1811).  Readers 
with  a  knowledge  of  German  may  be  referred  to  Stieve's 


204      GLANDS  IN  HEALTH  AND  DISEASE 

Entwicklung ,  Bau  and  Bedeutung  der  Keimdruesen- 
zwischenzellen  (development,  structure  and  significance  of 
the  interstitial  cells  of  the  gonads)  (J.  F.  Bergman, 
Munich) .  Voronoff  gives  an  account  of  his  experiments  in 
the  book  entitled  Life  (E.  P.  Dutton  &  Co.,  New  York). 
An  analysis  of  the  behavior  of  organs  after  transplantation 
is  discussed  by  L.  Loeb  (Journal  of  Medical  Research, 
volume  39,  page  189,  1918).  An  editorial  in  the  Journal 
of  the  American  Medical  Association  (volume  75,  page 
1070,  1920)  should  also  be  consulted.  J.  S.  Horsley  is 
the  author  of  an  instructive  article  on  the  "Suturing  of 
Blood  Vessels"  (Journal  of  the  American  Medical  Asso- 
ciation, volume  77,  page  117,  1921). 

THE  PANCREAS  AND  THE  LIVER.  ( See  also  the  "general" 
references  above.)  There  is  a  mass  of  literature  on  these 
organs;  we  can  refer  to  but  one  or  two  recent  articles. 
See,  for  example,  E.  P.  Joslin:  Diabetes  Mellitus  (Lea  & 
Febiger,  Philadelphia);  F.  M.  Allen:  Diabetes  Mellitus 
(Physiatric  Institute,  Morristown,  N.  J.) ;  E.  P.  Joslin: 
"The  Prevention  of  Diabetes  Mellitus"  (Journal  of  the 
American  Medical  Association,  volume  76,  page  8,  1921), 
wherein  we  find  the  cry  that  diabetes  is  a  penalty  for 
obesity;  J.  J.  E.  Macleod:  "The  Sugars  of  the  Blood" 
(Physiological  Reviews,  volume  1,  page  208,  1921),  a 
comprehensive  review  of  the  significance  of  blood  sugar; 
and  E.  Langfeld's  series  of  articles  on  the  significance  of 
a  physico-chemical  factor,  the  hydrogen  ion  content,  in  the 
regulation  of  blood  sugar  (Journal  of  Biological  Chem- 
istry, volume  46,  pages  381,  393,  403,  1921). 


REFERENCES  205 

THE  INTESTINAL  HORMONE.  (See  also  the  "general" 
references  above.)  Two  of  the  papers  by  Bayliss  and  Star- 
ling are  "The  Mechanism  of  Pancreatic  Secretion" 
(Journal  of  Physiology,  volume  28,  page  325,  1902)  and 
"The  Chemical  Regulation  of  the  Secretory  Process" 
(Proceedings  of  the  Royal  Society,  section  B,  volume  73, 
page  310,  1904).  The  books  on  physiology  by  Bayliss  and 
by  Starling,  referred  to  under  "general"  references,  give 
good  accounts  of  the  discovery  and  action  of  eecretin. 

THE  THYMUS,  SPLEEN,  MAMMARY  GLAND,  PINEAL  AND 
KIDNEY.  (See  the  "general"  references  above.)  Quite  a 
number  of  investigators  are  busying  themselves  with  the 
problem  of  the  function  of  the  thymus.  See,  for  example, 
J.  A.  Hammar  (Endocrinology,  volume  5,  page  543, 1921), 
E.  Uhlenhuth  (Endocrinology,  volume  3,  page  284,  1919), 
and  M.  B.  Gordon  (Endocrinology,  volume  2,  page  405, 
1919).  "Is  there  a  thymic  hormone?"  asks  Hoskins  (En- 
docrinology, volume  2,  page  241,  1918) ;  he  is  inclined  to 
answer  in  the  negative.  See,  also,  Crotti's  book,  The 
Thyroid  and  the  Thy  mm  (Lea  and  Febiger,  Philadelphia), 
and  an  editorial  in  the  Journal  of  the  American  Medical 
Association  (volume  77,  page  2063,  1921). 

N.  B.  Eddy  (Endocrinology,  volume  5,  page  461,  1921) 
reviews  the  functions  of  the  spleen.  Sir  Berkeley  Moyni- 
ham  (W.  B.  Saunders  Co.,  Philadelphia),  and  Pearce, 
Krumbhaar  and  Frazier  (J.  B.  Lippincott  Co.,  Philadel- 
phia) are  authors  of  books  dealing  with  the  spleen. 

Two  articles  on  the  pineal,  that  also  include  the  litera- 
ture, are  Horrax's  "Studies  on  the  Pineal  Gland"  (Ar- 


206      GLANDS  IN  HEALTH  AND  DISEASE 

chives  of  Internal  Medicine,  volume  17,  page  607,  1916)1 
and  Bailly  and  Jeliffe's  "Tumors  of  the  Pineal  Gland" 
(Archives  of  Internal  Medicine,  volume  8,  page  851, 1911). 
See,  also,  W.  E.  Dandy's  "The  Treatment  of  Brain  Tu- 
mors" (Journal  of  the  American  Medical  Association, 
volume  77,  page  1853,  1921).  Tilney  and  Kiley's  The 
Form  and  Functions  of  the  Central  Nervous  System 
(P.  B.  Hoeber,  New  York)  contains  a  mass  of  valuable 
material. 

THE  KELATION  OP  THE  DUCTLESS  GLANI>S  TO  ONE 
ANOTHER.  (See  also  the  "general"  references  above. ) 
Certain  angles  of  this  problem  are  taken  up  by  Stewart 
and  Rogoff  (American  Journal  of  Physiology,  volume  46, 
page  90,  1918),  and  Anon.  (Endocrinology,  volume  1, 
page  404,  1917). 

THE  INFLUENCE  OF  THE  DUCTLESS  GLANDS  ON  GROWTH 
AND  METABOLISM.  (See  the  "general"  references  above.)' 
Biedl  discusses  this  question  in  an  article  entitled  "The 
Significance  of  the  Internal  Secretions  in  Disturbances  of 
Metabolism  and  Digestion"  (Endocrinology,  volume  5, 
page  523,  1921). 

THE  NERVOUS  SYSTEM:  AND  THE  DUCTLESS  GLANDS. 
(See  also  the  "general"  references  above.)  A  mass  of 
literature,  much  of  it  of  a  pseudo-scientific  nature,  has 
accumulated  on  this  phase  of  the  subject.  Only  a  few  of 
the  books  and  pamphlets  will  be  referred  to.  See,  for  ex- 
ample, M.  Laignel-Lavastine :  The  Internal  Secretions  and 
the  Nervous  System  (Nervous  and  Mental  Disease  Pub- 


REFERENCES  207 

lishing  Co.,  New  York) ;  W.  Langdon  Brown:  The  Sympa- 
thetic Nervous  System  in  Disease  (Oxford  University 
Press,  London) ;  W.  B.  Cannon :  Bodily  Changes  in  Pain, 
Hunger,  Fear  and  Rage  (D.  Appleton  &  Co.,  New  York) ; 
G-.  W.  Crile :  A  Physical  Interpretation,  of  Shock,  Exhaus- 
tion and  Restoration  (W.  B.  Saunders  Co.,  Philadelphia) ; 
G.  W.  Crile:  Anoci-Association  (W.  B.  Saunders  Co., 
Philadelphia) ;  F.  W.  Mott:  War  Neuroses  (Oxford  Uni- 
versity Press,  London);  W.  Harris:  Nerve  Injuries  and 
Shock  (Oxford  University  Press,  London) ;  T.  R.  Elliot: 
"Ductless  Glands  and  the  Nervous  System"  (Brain,  vol- 
ume 35,  page  306,  1913);  N.  Pende:  "Endocrinopathic 
Contributions  to  Pathology"  (Endocrinology,  volume  3, 
page  329, 1919) ;  Y.  Henderson,  H.  W.  Haggard  and  R.  C. 
Coburn:  "The  Acapnia  Theory,  Now"  (Journal  of  the 
'American  Medical  Association,  volume  77,  page  424, 
1921);  C.  W.  Crile:  "The  Mechanism  of  Shock  and  Ex- 
haustion" (Journal  of  the  American  Medical  Association, 
volume  76,  page  149,  1921);  H.  H.  Dale:  "The  Nature 
and  Cause  of  Wound  Shock"  (Harvey  Lectures,  1919- 
1920,  page  26;  J.  B.  Lippincott  Co.,  Philadelphia,  pub- 
lishers) ;  F.  X.  Dereum:  Clinical  Manual  of  Mental  Dis- 
eases (W.  B.  Saunders  Co.,  Philadelphia). 

An  article  by  Cannon  that  reviews  much  of  his  work  on 
the  adrenals  may  be  found  in  the  American  Journal  of 
Physiology,  volume  50,  page  399,  1919;  literature  is  ap- 
pended. For  articles  by  Stewart  and  Rogoff  see,  among 
others,  the  American  Journal  of  Physiology,  volume  46, 
page  89,  1918,  volume  48,  pages  22  and  397, 1919 ;  Journal 
of  Pharmacology  and  Experimental  Therapeutics,  volume 
13,  pages  95,  167,  183,  361,  and  397,  1919,  and  volume 


208       GLANDS  IN  HEALTH  AND  DISEASE 

14,  page  343,  1919;  American  Journal  of  Physiology,  vol- 
ume 51,  page  366,  1920,  and  volume  52,  page  304,  1920; 
Journal  of  Pharmacology  and  Experimental  Therapeutics, 
volume  16,  page  71,  1920,  and  volume  17,  page  227,  1921 ; 
and  the  review  by  Stewart,  "Adrenal  Insufficiency"  (En- 
docrinology, volume  5,  page  283,  1921),  which  includes 
many  references. 

ORGANOTHERAPY.  Consult  Osborne's  Therapeutics  (W. 
B.  Saunders  Co.,  Philadelphia),  and  H.  K.  Harrower's 
Practical  Hormone  Therapy  (P.  B.  Hoeber,  New  York). 
The  Wilson  Laboratories,  Chicago,  111.,  publish  a  quarterly, 
The  Autacoid  and  Suture,  which  includes  articles  on  the 
subject.  The  dangers  involved  in  the  use  of  glandular 
extracts  is  pointed  out  by  M.  P.  Rucker  and  C.  C.  Haskell 
(Journal  of  the  American  Medical  Association,  volume  76, 
page  1390,  1921). 

PLANT  HORMONES.  The  literature  on  the  subject  is 
very  meager.  See,  for  example,  J.  Loeb:  "Hormones  in 
Bryophyllum"  (Science,  volume  44,  page  210, 1916) ;  E.  J. 
Eussell:  Soil  Conditions  and  Plant  Growth  (Longmans, 
Green  &  Co.,  London) ;  E.  W.  Thatcher:  The  Chemistry 
of  Plant  Life  (McGraw-Hill,  New  York). 

A  FEW  CLASSICAL  BOOKS  AND  PAPERS 

Johannes  Miiller:  Lehrbuch  der  Physiologie,  volume  1 

(Koblenz,  1844). 

"Miiller  points  out  that  the  process  of  secretion  consists 
of  two  phases, — the  production  of  certain  materials,  and 
the  casting  out  of  these  materials  upon  a  surface  either  in 


REFERENCES  209 

the  interior  or  upon  the  exterior  of  the  body.     The  first 
phase  he  called  'secretion/  the  second,  'excretion.' ): 

A.  A.  Berthold:  "Transplantation  der  Hoden"    (Archiv 
fur  Anatomie  und  Physiologic,  page  42,  1849). 
Berthold  removed  the  testicles  from  cocks  and  grafted 
them  to  other  parts  of  the  body.     He  observed  that  "the 
animals  retained  their  male  characteristics  in  regard  to 
voice,  reproductive  instinct,  fighting  spirit,  and  growth 
of  comb  and  wattles." 

Thomas  Addison :  On,  the  Constitutional  and  Local  Effects 
of  the  Disease  of  the  Suprarenal  Bodies  (London,  1855). 
An  account  of  the  now  well-known  "Addison's  Disease." 

Claude  Bernard:  Legons  sur  les  proprietes  physiologiques 
et  les  alterations  pathologiques  des  liquides  de  I'organ- 
isme  (Bailliere  et  Fils,  Paris,  1859). 
Here  we  find  the  first  clear  accounts  of  glandular  or- 
gans that  distribute  their  products  by  means  of  the  blood 
stream.     The  very  name  "internal  secretion"  is  due  to 
this  illustrious  Frenchman. 

Theodore    Kocher:    "Ueber    Kropfexstirpation   und    ihre 
Folgen"    (Archiv  fur  Iclinische  Chirurgie,  volume  29, 
1883). 
Myxedema  is  due  to  the  loss  of  the  functional  activities 

of  the  thyroid  gland. 

M.  Schiff:  "Bericht  iiber  eine  Versuchsreihe  betr.  die 
Wirkungen  d.  Exstirpation  der  Schildriise"  (Archiv 
•fur  experiment  elle  Pathologic  und  Pharmakologie, 
volume  18,  1884). 


210       GLANDS  IN  HEALTH  AND  DISEASE 

Epoch-making  experiments  on  the  effects  of  the  removal 
of  the  thyroid. 

P.  J.  Mobius:  Schildruse  theorie  (Schmidts  Jahrbiicher, 

volume  210,  page  237,  1886). 

The  opinion  is  expressed  that  Basedow's  disease  depends 
on  an  abnormally  increased  activity  of  a  ductless  gland. 

P.  Marie:  "Sur  deux  cas  d'acromegalie,  hypertrophie  sin- 
guliere  non  congenitale  des  extremites  superieures,  in- 
ferieures  et  cephaliques  (Revue  de  mededne,  page  298, 
1886). 
The  discovery  that  acromegaly  is  a  disease  due  to  the 

pituitary. 

Brown-Sequard :  "Des  effets  produits  chez  1'homme  par  des 
injections  sous-eutanees  d'un  liquide  retire  des  testi- 
cules  frais  de  cobaye  et  de  chien"  (Comptes  rendus  de 
la  societe  de  biologie,  volume  41,  page  415,  1889). 
"Brown- Sequard  injected  the  juice  of  the  testicle  sub- 
cutaneously  into  his  own  body  and  observed  an  increase  in 
corporeal  and  mental  powers  that  he  attributed  to  the 
influence  of  these  injections."    The  beginning  of  modern 
organotherapy,  or  treatment  by  means  of  glandular  ex- 
tracts. 

J.  von  Mering  and  0.  Minkovski :  "Diabetes  mellitus  nach 
Pankreas    exstirpation"     (Archiv    fur    experimentelle 
Pathologie,  volume  26,  page  371,  1889). 
The  complete  removal  of  the  pancreas  results  in  severe 

diabetes. 


REFERENCES  211 

E.  Gley:  "Sur  les  effets  de  Pextirpation  du  corps  thy- 
roide"  (Comptes  rendus  de  la  societe  de  biolotfie,  page 

843,  1891). 
Tetany  is  due  to  the  removal  of  the  parathyroids. 

G.  Oliver  and  E.  A.  Schafer :  "The  Physiological  Effects  of 
Extracts    of    the    Suprarenal    Capsules"    (Journal    of 
Physiology,  volume  18,  page  230,  1895). 
An  injection  of  an  extract  of  the  adrenal  glands  in- 
creases the  blood  pressure. 

E.  Baumann :  "Ueber  das  normale  Vorkommen  von  Jod  im 
Tierkorper"  (Z eitschrift  fur  physiologische  Chemie> 
volume  21,  page  319,  1896).  , 

The  discovery  that  the  element  iodine  is  a  normal  con- 
stituent of  the  body. 

J.  Takamine:  "The  Isolation  of  the  Active  Principle  of 
the  Suprarenal  Gland"  (Proceedings  of  the  Physiologi- 
cal Society,  in  the  Journal  of  Physiology,  volume  27, 
page  xxix,  1901). 
An  account  of  the  isolation  of  adrenaline. 

A.  Frohlich:  "Fall  von  Tumor  der  Hypophysis  cerebri 
ohne    Akromegalie"     (Wiener    Jclinische    Rundschau, 
1901). 
A  disease  is  described  which  is  the  reverse  of  acrome- 

galy — that  is,  it  is  due  to  a  diminished  activity  of  the 

pituitary. 

W.  M.  Bayliss  and  E.  H.  Starling;  "The  Mechanism  of 
Pancreatic  Secretion"   (Journal  of  Physiology,  volume 
28,  page  325,  1902). 
The  hormone,  secretin,  is  described. 


212       GLANDS  IN  HEALTH  AND  DISEASE 

J.  S.  Edkins :  "The  Chemical  Mechanism  of  Gastric  Secre- 
tion"   (Journal  of  Physiology,  volume  34,  page   133, 
1906). 
Extracts  of  the  lining  of  the  stomach  cause  an  increased 

formation  of  gastric  juice. 

H.  Gushing:  The  Pituitary  Body  and  Its  Disorders  (J.  B. 
Lippincott  Co.,  Philadelphia,  1912). 
A  classic  on  the  subject. 

E.  C.  Kendall:  "The  Isolation  of  the  Iodine  Compound 
Which  Occurs  in  the  Thyroid"  (Journal  of  Biological 
Chemistry ,  volume  39,  page  125,  1919). 
The  isolation  of  "thyroxin,"  the  active  principle  of  the 

thyroid  gland. 


INDEX 


Alel,  56,  81,  203 
AUlard,  93 
Acromegaly,  48,  62 

—  case  of,  65 

—  cure  in,  63 

—  symptoms  in,  62 
Addison's  disease,  73 
Adrenal  extract,  effect  of,  75 
Adrenal    glands,    10,    70-88 

—  cortex  of,  77 

—  description  of,  70 

—  history,    70 

—  in  shock,  177 

—  medulla  of  the,  79 

—  removal  of,  71 

—  summary  of  function,  88 

—  vitamine  B  and,  10.  See  Ad- 

dison's disease ;  Adrenal 
extract;  Adrenaline;  Graft- 
ing; Hyperadrenalism ; 
Nervous  system  and  the 
ductless  glands;  Sympa- 
thetic nervous  system 
Adrenaline,  78,  79 

—  blood    and,    85 

—  chemistry  of,  79 

—  derived   from  tyrosine,   79 

—  determination  of,  85,  163 

—  emotional   excitement,   pain, 

asphyxia  and,  162 

—  function  of,  169,  178,  188 

—  preparation   of,   81 

—  properties  of,  82 

—  sugar  metabolism  and,  86 
— •sympathetic  nervous  svstem 

and,  87,  161 

—  uses    of,    83.    See    Adrenal 

glands ;     Nervous     system 
and  the  ductless  glands 


Allen,  19,  125,  204 
Amnesia,    183 
Anoci-association,  175 
—  operations  and,  176 
Anrep,  199 
Atwater,  37 

Bailty,  206 

Bandler,  198 

Basedow's  disease,  15,  31.  See 

Exophthalmic  goiter 
Barger,  203 
Barker,  203 
Baumann,  211 
Basal  metabolism,  39,  41 
Bayliss,  4,   127,   129,   132,  133, 

144,  192,  198,  205,  211 
Beard,  183 
Bell,   202 
Benedict,  37,  201 
Berman,  198 
Bernard,  Claude,  118,  119,  120, 

209 

Berthold,  209 

Biedl,  78,  97,  141,  146,  197,  206 
Bile,  116 

Boothby,  41,  200,  201,  202 
Bottomley,  190 
Braun,  84 
Broum,  207 
Brou-n-Sequard,   72,   91-92,   97, 

98,  102,  114,  185,  186,  210 
Budington,  194 
Burton-Opitz,  198 

Carbohydrate  metabolism,  116 
Carbon  dioxide,    119 
Carlson,    173,    181 
Cassan,  70 


213 


214 


INDEX 


Castration,  93 

—  effects  of,  93 

—  mental  development  and,  94 

—  sex    characteristics    and,    95 
Catalysts,  12 

Charcot,  183 

Clark,  61 

Cobb,  159,  183,  198 

Cretinism,   15,   18,  22 

Crile,  83,  158,  174,  182  183,  200 

207 

Crotti,  200,  205 
Gushing,  48,  49,  51,  57,  64,  65, 

66,  182,  202,  212 

Dale,  207 
Dandy,  206 
Dane,    183 
Darwin,  69 
de  la  Paz,  161 
Dementia  precox,  84 
Dercum,  207 
Descartes,  100 
Diabetes,  7,   120,   121 

—  Allen  treatment  for,  125 
Doege,   146 
Drummond,   199 

Du  Bois,  39,  201 
Ductless  glands,  2,  3,  4 

—  influence  of,  on  growth  and 

metabolism,  156 

—  nervous  system  and,  158 

—  relation  of,  to  one  another, 

147.  See  Endocrine 
glands;  Glands,  of  inter- 
nal secretion 

Dutcher,  9,  28,  199 

Dyspituitarism,   64 

Eddy,   140,  205 
Edkins,  133,  134,  212 
Eidelsberg,  74 
Elliot,  207 
Endemic  goiter,  27 
Endocrine    glands,    3,    4.    See 

also  Ductless  glands 
Enriquez,  131 


Enzymes,  3,  11 
Epiphysis.     See  Pineal 
Eppinger,  148,  150 
Errera,  192 
Eunachoids,  95 
Eustachius^  70 
Exophthalmic  goiter,  15,  31 
-—symptoms  in,  31 

—  treatment  of,  33 

Falta,  18,  93,  148,  160,  197 

Ferments.     See  Enzymes 

Finney,  141 

FisKberg,  197 

Foa,    141 

FoUn,  86 

Frazier,  205 

Friedmann,  81,  203 

Frotich,  211 

Fulbert,  93 

Fulton,  200 

Funk,  9 

Furth,  81 

Gastric  secretion,  133 
Gigantism,  63 
Glands,   2,    3 
Glandular  extracts,  187 

—  conflicting  results  with,  187. 

See  Organotherapy 
Glands,    of    internal    secretion, 

3,  6.  See  Ductless  glands; 

Endocrine    glands 
G-ley,  43,  47,  151,  162,  197,  211 
Glucose,  117 
Glycogen    117 
Ooetsch,  152 
Goiter.    See    Endemic    goiter; 

Exophthalmic  goiter 
Gordon,  205 
Grafting,    76,    97,    108.         See 

Transplantation  of  tissues 
Graves's   disease,    15,    31,    158. 

See  Exophthalmic  goiter 
Growth,    influence    of    ductless 

glands  on,  156 


INDEX 


215 


Gruber,  161 

Gudernatsch,  19,  20,  137 
Gull,  16 


Haber,  12 
Hahnemann,  185 
Hallion,  131 
Hammar,  205 
Hammond,  145 
-Harris,  207 
Harrow,  9,  201 
Harrower,  198,  200 
Haskell,  208 
Hayliurst,  202 
Heloise,  93 
Henderson,  119,  207 
Herter,  51 
Hertzler,   159 
Hippocrates,  185 
Histidine,   56 
Hogben,  201 
Hopkms,  136 
Hormones,  5,  6 

—  composition    of,    8 

—  in  plant,  190 

—  relation  of  vitamines  to,  8- 

11 

—  relation   of   amino-acida  to, 

11 

Horraao,  141,  205 
Horsley,  204 
Howell,  54,  198 
Hunger,  nature  of,  173 
Hyper-adrenalism,  77 
Hyperpituitarism,  56,  61 

—  and  giants,  64 
Hyperthyroidism,   15,   159.   See 

Exophthalmic   goiter 
Hypophysis  cerebri,  47.  See  Pit- 
uitary 
Hypopituitarism,  50 

—  and  the  dwarf,  51 
Hypothyroidism,  15,  160 

—  symptoms  of,  17.  See  Myxe- 

dema;  Cretinism 
Hysteria,    183 


Intestinal  hormone,  127-134 

—  influences  flow  of  pancreatic 

juice,  128.     See  Secretin 
Intestine,    small,    digestion    in, 

127 

Islands  of  Langerhans  and  dia- 
betes, 121 

Interstitial   cells,   90,   97,    102, 
103,   104 

—  old  age  and,  98 
Iodine,  in  the  thyroid,  25 

—  an  essential  element  of  the 

body,  29 

Jaboulay,  77 
James,  173 
Janet,  183 
Jeliff e,  206 
Joslin,  204 

Kahn,  72,  199 

Keeble,  192 

Kellaway,  199 

Kendall,  8,  24,  25,  26,  27,  28, 

188,  200,  212 
Kidney,   internal   secretion   of, 

146 

Kimball,  29,  201 
Klinger,  30 
Koch,  45 

Kocher,    16,   34,   209 
Kolber,  107 
Krumbhaar,  205 

Latey,   201 

Laignel-Lavastine,  206 
Langfeldt,  124,  204 
Lavoisier,  36 
Le  Page,  130 
Lichtenstem,  107 
Liver,  116 

—  a  ductless  gland,  118 

—  carbohydrate         metabolism 

and,  116 

—  glycogen     and,      117.       See 

Claude      Bernard;      Dia- 
betes ;   Pancreas ;  Urea 


216  INDEX 


Loeb,  J.,  19,  201,  208 
Loeb,  L.,  204 
Lovand,  112 
Luciani,  132,  198 
Lusk,  39 
Lyman,  161 

MacCalUm,  198,  202 

MacCarrivon,  10,  199 

MacCarthy,  201 

Mackenzie,  145 

¥o,cioe<Z,  55,  189,  198,  204 

Magnums-Levy,  160 

Mammary  Gland,  144-145 

Marie,  48,  61,  210 

Marine,  29,  201 

Marshall,  203 

Mathews,  73,  198 

lf<M/o  brothers,  25 

Mat/o,  (7.,  34 

Means,  201 

MecfceZ,  71 

Meltzer,  86,  161 

Mendel,  51 

Mendenhall,  161 

<y.   Mering,   116,   120,  210 

Metabolism,  definition  of,  36 

—  in  thyroid  disease,  40 

—  influence  of  ductless  glands 

on,   156.   See  Basal  meta- 
bolism; Surface  area 

Minkowski,   116,   120,   125,  210 

MoUus,  183,  210 

Monkey  Glands,  111 

Mott,  207 

Moyniham,   205 

Miiller,  208 

Murlin,  201 

Myers,  199 

Myxedema?  15,  23 

—  symptoms  in,  23 

—  treatment  of,  23 

Ttagel,  111 

Nervous  system  and  the  duct- 
less glands,  158-184 


Nervous  system,  sexual  glands 
and,  181.  See  Adrenaline; 
Adrenal  glands;  Cannon; 
Crile;  Stewart 

Xioe,  161 

t?.  Noorden,  125 

OeJisner,  200,  202 
Old  age,  98,  102,  105 

—  the  Steinach  operation   and, 

106 

—  the  Voronoff  operation  and, 

109 

—  Brown-Sequard's  experi- 

ments, 186 
Oliver,  53,  80,  211 
Ord,  16 
Organotherapy,    185-189.       See 

Glandular  extracts 
Organs  of  reproduction,  7,  89- 

114 

—  proof   of   internal   secretion, 

89 

—  two  types  of  secretion,   90. 

See  also  Brown-Sequard; 
Castration;  Eunachoids; 
Grafting;  Interstitial 

cells;  Monkey  glands ;  Old 
age;  pubertas  precox;  Re- 
juvenation; Steinach;  Vas 
deferens;  Voronofi 

Osborne,  0.  T.,  208 

Osborne,  T.  B.,  51 

Osgood,  161 

Osier,  198 

Pancreas,   7,   115 

—  blood  sugar  and,  122-124 

—  internal    secretion    of,    115, 

120,   121.       See  Diabetes; 

Islands     of     Langerhans; 

Liver 

Pancreatic  extract,  189 
Parathyroids,    43-46.    See   Tet- 

any 

Paton,  197 
Pavlov,  128,  133,  139 


INDEX 


217 


Pearce,  205 
Pende,  207 
Pettenkofer,   37 
Pickering,    193 
Pineal,    140-144 

—  a  case  of  disease  of,  142 

—  clinical   features   of   disease 

of  144 

—  effect  of  extract  of,   141 

—  evidence    in    favor    of    hor- 

mone in,  141 

—  removal  of,  141 
Pituitary,  47-69 

—  description  of,  47 

—  difficulty      in      interpreting 

data,  56,  57 

—  function  of,  52,  53 

—  removal    of,    49.        See   also 

Acromegaly;  Dwarf;  Dys- 
pituitarism;  Hyperpitui- 
tarism;  Hypopituitar- 
ism;  pituitary  extract; 
Pituitrin;  Tethelin 

Pituitary  extract,  use  of,  58, 
60,  145 

Pituitrin,  54,  55 

Plant  hormones,  190 

Polk,    68 

Pollock,  183 

Popielski,    132 

Psychasthenia,  184 

Psycho-analysis,  182 

Ptyalin,  3 

Pubertas  precox,  113 

Quackery  in  medicine,  59 

Rejuvenation,  107,  110.  See  Old 
age 

Relation  of  ductless  glands  to 
one  another,  147-155 

Reproductive  organs.  See  Or- 
gans of  reproduction 

Richardson,   200,   202 

Ril&y,  206 

Robertson,  52,  53,  152,  203 


Rogoff,  162,  165,  168,  169,  178, 

179,  180,  206,  207 
Rosa,  37 
Rubner,  37 
Rucker,  208 
Rudinger,  148 
Russell,  208 

Sacchi,   114 

Sajous,  206 

Schafer,  53,  71,  78,  80.  197,  211 

Schiff,  15,  16,  17,  209' 

Sciplades,  137 

Secretin,  6,   127-134 

—  how  discovered,  129-131 

—  objections    to    Bayliss    and 

Starling's  work  on,   132 

—  origin   of  name,    131.       See 

Bayliss;  Intestinal  hor- 
mone; Pavlov;  Starling 

Sexual  glands.  See  Organs  of 
reproduction 

Shell-shock,  182.  See  Shock 

Shock,  174 

—  kinetic  theory  of,   175,   177. 

See  Shell-shock 
Shohl,  161 

Skin,  internal  secretion  of,  146 
Spleen,    138-140 

—  extirpation  of,   139 

—  function    of,    138 

—  gives  rise  to  internal  secre- 

tion,  140 
Starling,  4,  127,  129,  132,  134, 

198,  205,  211 
Steinach  92,   99,   101-107,   108, 

111,  112,  203 
Stewart,    151,    154,    162,    165, 

167,  168,  169,  178,  179,  180, 

181,    199,    203,    206,    207, 

208 

Sti-eve,  203 
Surface  area  and  metabolism, 

38 

Sweetbread.  See  Pancreas 
Swingle,  137 
Sympathetic  nervous  system,  82 


218 


INDEX 


Tdkamine,  81,  211 

Tandler,  96 

Temperature,       constancy       of 

body,  37 

Testicular  extracts,  use  of,  186 
Tetany,    43 
Tethelin,  53,  152 
Thatcher,  208 
Thymic  asthma,   138 
Thymus,  135-138 

—  effect     of  extract,  138 

—  function  of,   136.     See  Thy- 

mic asthma 

Thyroid,  14-42.  See  Basal  me- 
tabolism; Cretinism;  Ex- 
ophthalmic goiter;  Hyper- 

thyroidism;    Hypothyroid- 

ism;      Iodine;      Kendall; 

Myxedema;  Thyroxin 
Thyroid  feeding,  19,  20,  23 
Thyroid  gland  transplantation, 

21 
Thyroid  hormone,  isolation  of, 

25 

Thyroidectomy,  15 
Thyroxin,  26-28,  187,  188 
TUney,  141,  206 
Transplantation  of  tissues,  99, 

104.    See   Grafting 
Tucker,  207 


Uhlenhuth,  136,  156,  206 
Underhill,  154 
Urea,  118 

Vas  deferens,  90,  103,  104 

—  operative  technique,  105 
Vincent,    80,    197 
Vitamines,  9 

—  secretin,  and,  134 
Voegtlm,   134,   199,  202 
Voit,    37 

Foronof,   77,   92,   98,   99,   105, 
107-112,  204 

War,  moral  substitutes  for,  173 

Washbum,  161 

Weil,   197 

Wells,   H.   G.,    (the   novelist), 

128 
Wells,  H.  G.,  (the  pathologist), 

199 

Wertheimer,  130 
Wright,  161 

X-rays  and  the  organs  of  re- 
production, 96,  104,  106 

Zandren,  141 
Zuelzer,  123 
Zunz,  37 


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